CADTH Reimbursement Review

Dupilumab (Dupixent)

Sponsor: sanofi-aventis Canada Inc.

Therapeutic area: Atopic dermatitis, pediatrics

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks.

Source: Sponsor’s submission package for review of dupilumab, dupilumab product monograph, and sponsor’s Summary of Clinical Evidence.^1-3

Introduction

Disease Background

Atopic dermatitis is a chronic, relapsing, inflammatory skin condition characterized by intense itching, red and swollen skin, papules, excoriation, rash, and serous exudation.^4,5 In pediatric patients, atopic dermatitis tends to present in the face, extensor extremities, and cheeks. Itching leads to frequent scratching and may result in skin infections and thickening of the skin.^4,6 Atopic dermatitis is estimated to affect 15% to 20% of children globally.^7,8 In Canada, the lifetime prevalence of atopic dermatitis is up to 17% of the population.⁹ Pediatric patients with atopic dermatitis experience substantial symptom burden, poor sleep quality, reduced health-related quality of life (HRQoL), and frequent comorbidities.^10-20 Patients with atopic dermatitis are at an increased risk of developing other atopic diseases such as asthma, food allergy, allergic rhinitis, conjunctivitis or rhinoconjunctivitis,^11-14,21 attention-deficit/hyperactivity disorder, and autism spectrum disorder.^4,14,15 The care required for these pediatric patients can be time-consuming and interferes with day-to-day activities,²² leading to increased feelings of caregiver anxiety, depression, worry, and helplessness.²³ Managing atopic dermatitis adds a substantial financial burden on health care systems, society, and families.^22,24-30 The most commonly used instruments in clinical trials to measure severity are the Investigator’s Global Assessment (IGA), Eczema Area and Severity Index (EASI), Physician’s Global Assessment, body surface area (BSA) affected, and Scoring Atopic Dermatitis (SCORAD).³¹

According to the clinical experts consulted by CADTH, the goals of treatment for pediatric patients with moderate-to-severe atopic dermatitis are to reduce symptom severity and improve HRQoL with minimal adverse effects as well as reduce caregiver burden. While there is no cure for atopic dermatitis, several therapeutic options are available. The treatment paradigm consists of education regarding general skin care and identifying and avoiding triggers.³² Treatments include moisturizers and topical anti-inflammatory drugs; however, these are noted as being time-consuming to administer and can have side effects, which can lead to low compliance and refractory disease. Phototherapy and systemic immunosuppressants (off-label use) are occasionally used in patients with severe disease who do not respond to topical therapy or in addition to topical therapy, though use of the latter is uncommon in patients aged younger than 5 years and rare in patients aged younger than 2 years, and these therapies have significant limitations and intolerable adverse effects.³²

Dupilumab (Dupixent) is a recombinant human immunoglobulin G4 monoclonal antibody and is indicated for the treatment of patients aged 6 months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, and can be used with or without topical corticosteroids (TCSs).¹ For patients aged 6 months to 11 years, the drug is available as prefilled syringes containing either 200 mg or 300 mg dupilumab for subcutaneous (SC) injection with age-based and weight-based dosing (Table 1).¹ Dupilumab was previously reviewed by CADTH for the treatment of patients aged 12 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, and received a recommendation from the CADTH Canadian Drug Expert Committee to be reimbursed with clinical criteria and conditions.³³ Currently, the sponsor has requested reimbursement be expanded to include younger patients.²

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of dupilumab, 200 mg or 300 mg, for SC injection in the treatment of patients aged 6 months to younger than 12 years with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

CADTH received input from 3 patient groups: the Eczema Society of Canada and a joint input from the Canadian Skin Patient Alliance and Eczéma Québec. The inputs were provided for a previous CADTH submission for dupilumab in 2021, where the indication was for patients aged 6 years to 11 years with moderate-to-severe atopic dermatitis. No new patient input was received for the current review of dupilumab.

According to the patient groups, the symptoms of atopic dermatitis negatively affect individuals and their families and interfere with sleep, contribute to missed school and activities, psychosocial issues, and result in an increased risk of mental health problems. The groups stated that quality of life, access to care, and disease management are concerns that are associated with significant psychosocial, educational, financial, and occupational burden. The authors of the joint input stated that the complex, time-consuming skin treatment routines and other associated burdens make managing the disease very challenging and exhausting. Furthermore, comorbidities associated with pediatric atopic dermatitis require multidisciplinary management and screening to manage the disease. Patients seek a treatment that safely and effectively manages symptoms, reduce flares, and improves the quality of life of both patients and caregivers.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts explained that current topical treatments for atopic dermatitis do not work for all patients, can be burdensome and have low adherence, can have side effects, and some are expensive and not covered by insurance plans. Likewise, systemic immunosuppressants are associated with numerous adverse effects, are poorly tolerated, and require regular blood monitoring. Phototherapy can be inaccessible to patients and is often not feasible for young children.

According to the experts, dupilumab would be used as a second-line therapy after failure of an adequate trial with topical therapies (e.g., TCSs, topical calcineurin inhibitors [TCIs]), but before systemic immunosuppressants due to their poor safety profile. Both experts believed that it would be inappropriate to require either phototherapy or systemic immunosuppressant failure in patients aged younger than 12 years before being eligible for dupilumab.

Both clinical experts indicated that patients who could receive dupilumab would be identified based on clinician examination and judgment, taking into account disease severity and inadequate response to topical therapies. They also stated that patients with severe disease that is refractory to topical therapy and has a major impact on their HRQoL are most in need of effective treatment.

The experts indicated that outcomes used in clinical trials can help to gauge treatment response but are not typically used in clinical practice, except when required by a health insurer. Instead, patient assessments are usually a combination of discussion with the patient and caregiver and examination of the skin. It was noted that patients receiving dupilumab can have a delayed response and that it would be reasonable to assess patients for response to treatment approximately 3 months to 6 months after initiating treatment with dupilumab then every 6 months thereafter.

According to the experts, discontinuation of dupilumab should be considered if there is a lack of response to treatment (e.g., no improvement in rash, itch, or HRQoL) or there are intolerable adverse effects. One clinician added that patients often continue to use topical treatments alongside dupilumab, and that would not be a reason to discontinue treatment. Although it is possible to outgrow childhood atopic dermatitis, both experts explained that this is less likely for patients with severe disease, other atopic comorbidities, or persistent and generalized atopic dermatitis. It was suggested that a trial of increasing the time between injections once disease control is achieved with the plan to stop dupilumab altogether could be an option discussed and decided on between the treating physician, patient, and caregiver, though stopping the drug should not be forced.

The experts agreed that a specialist (i.e., dermatologist) would prescribe dupilumab, and it would be initiated in a hospital or community clinical setting. In situations where there is limited access to a dermatologist or pediatric dermatologist, the experts suggested that a general pediatrician, allergist, immunologist, or a physician with training in atopic dermatitis could prescribe the drug.

Clinician Group Input

Clinician group input was provided by the Canadian Dermatology Association. The input provided was largely aligned with that of the clinical experts consulted by CADTH. According to the clinician group input, patients can experience long wait times before seeing a specialist while their atopic dermatitis remains poorly controlled. They also noted that most dermatologists in Canada are not trained in, nor are comfortable, managing pediatric safety laboratory results in the context of systemic immunosuppression. It was highlighted in the input that dupilumab is the only systemic treatment for atopic dermatitis indicated for this age group and does not carry the same risk profile as traditional immunosuppressants. The clinician group stated that an ideal treatment would have a proven safety record in this age group and would also be able to reduce symptoms and improve sleep, concentration at school, and the overall quality of life for both patients and caregivers. It was also emphasized that a trial of systemic immunosuppression should not be a prerequisite for dupilumab coverage in patients aged 6 months to 5 years. The authors of the input highlighted remote Indigenous communities as being vulnerable groups in which individuals with poorly controlled atopic dermatitis tend to be at higher risk for chronic skin diseases and secondary infections and that dupilumab can be a good option for patients in these communities.

Drug Program Input

The drug programs requested input from the clinical experts regarding whether the initiation criteria should reflect the different trial inclusion criteria (specifically, moderate versus severe disease), how an adequate trial of topical prescription therapies is defined, if reimbursement criteria for this population (younger than 12 years) should be aligned with the current criteria for patients aged 12 years and older, and who would prescribe the drug.

The clinical experts stated that it would be reasonable to expect that dupilumab would work similarly in patients with moderate atopic dermatitis as those with severe atopic dermatitis who are aged 6 years to younger than 12 years, based on results from age groups younger and older that included patients with moderate disease. They also noted that the literature supports consideration of dupilumab treatment for some patients with moderate atopic dermatitis and an EASI score less than 16 with severe lesions that are not widespread or are localized to special areas (e.g., hands, feet, scalp).^34,35 According to the experts, an adequate trial of topical prescription therapies would include TCSs or TCIs once or twice daily for at least 4 weeks and a patient who continues to experience persistent moderate-to-severe dermatitis that substantially impacts their quality of life is considered to have inadequately controlled disease. Both clinical experts agreed that patients aged 6 months to younger than 12 years should not be required to try systemic immunosuppressants or phototherapy before accessing dupilumab. Furthermore, if they have initiated and are responding to dupilumab before becoming 12 years old, they should be allowed to continue using dupilumab without having to try other therapies once reaching the age of 12 years. In general, the clinical experts felt that the continuation criteria issued by the CADTH Canadian Drug Expert Committee for dupilumab for patients aged 12 years and older were acceptable for patients aged 6 months to younger than 12 years. They noted that although some patients may not experience a 75% reduction in Eczema Area and Severity Index score (EASI-75), they still show a meaningful improvement from baseline, and felt this should not preclude patients from continuing dupilumab. Lastly, the experts agreed that a specialist (i.e., dermatologist) would prescribe dupilumab and in situations where access to dermatologists or pediatric dermatologists is limited, a general pediatrician, allergist, immunologist, physician with training in atopic dermatitis, or family physician in conjunction with a specialist could do so.

Clinical Evidence

Pivotal Studies and Randomized Controlled Trial Evidence

Description of Studies

Two phase III, double-blind (DB) randomized controlled trials (RCTs) (the LIBERTY AD PRESCHOOL part B trial, N = 162, and LIBERTY AD PEDS trial, N = 367) assessed whether dupilumab with TCSs reduced a patient’s IGA score to 0 or 1 compared to placebo with TCSs after 16 weeks of treatment in patients aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis (LIBERTY AD PRESCHOOL trial) or aged 6 years to younger than 12 years with severe atopic dermatitis (LIBERTY AD PEDS trial). Patients enrolled in both studies had disease that was not adequately controlled with topical prescription therapies. Key secondary outcomes included the proportion of patients with an EASI-75, percent change from baseline in EASI score, and percent change from baseline in weekly average of daily worst itch numeric rating scale (NRS) score at week 16. In both studies, HRQoL outcomes were assessed as other secondary outcomes, and included the Dermatitis Family Impact (DFI) questionnaire, Children’s Dermatology Life Quality Index (CDLQI), and Infants’ Dermatitis Quality of Life Index (IDQOL), the last of which was only assessed in the LIBERTY AD PRESCHOOL trial.

The IGA is a 5-point scale that provides a global clinical assessment of atopic dermatitis severity ranging from 0 (clear) to 4 (severe atopic dermatitis). A decrease in score relates to an improvement in signs and symptoms. The EASI is a tool used in clinical trials to assess the severity and extent of atopic dermatitis. For this scale, 4 disease characteristics of atopic dermatitis (erythema, thickness, scratching, and lichenification) are assessed for severity by the investigator on a scale of 0 (absent) to 3 (severe), and the scores are added together for each of the 4 body regions (head, arms, trunk, and legs). The area affected by atopic dermatitis is assessed as a percentage by each body region and is converted to a score of 0 to 6, where the area is expressed as 0 (none), 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). Each of the body area scores are multiplied by the area affected. Therefore, the total EASI score ranges from 0 points to 72 points, with a higher score indicating worse disease severity. The itch NRS is a tool that patients use to report the intensity of their itch with a daily recall period. Patients rate their overall (average) and maximum intensity of itch experienced during the previous 24 hours, based on a scale of 0 (no itch) to 10 (worst itch imaginable). The DFI is an atopic dermatitis-specific, self-administered, 10-item questionnaire designed to assess the impact of disease on the quality of life of families of children affected by disease based on a 1-week recall. Responses are scored on a 4-point Likert scale (from 0 to 3) and the total score ranges from 0 to 30, with higher scores indicating greater impairment in family quality of life. The CDLQI is a questionnaire completed by the child (aged 3 years to 16 years) designed to measure the impact of any skin disease on the quality of life with a recall period of 7 days. It consists of 10 questions asking about the impact of a skin disease on the life of the affected child, including symptoms, embarrassment, friendships, clothes, playing, sports, bullying, sleep, and impact of treatment. Each response is rated on a 4-point Likert scale (from 0 to 3) and the total score ranges from 0 to 30, with higher scores indicating a greater degree of impairment in HRQoL. The IDQOL is a questionnaire designed to measure the impact of the skin disease on the quality of life of infants and preschool children aged younger than 4 years. It consists of 10 questions that examine the impact of the disease on the life of the affected child and includes, but is not limited to mood, sleep, and daily activities. Each question is rated on a 4-point Likert scale (from 0 to 3) and the total score ranges from 0 to 30, with higher scores indicating worse quality of life.

Overall, baseline patient characteristics were balanced among treatment groups in both trials. In the LIBERTY AD PRESCHOOL trial, the mean age of patients was 3.8 years, there were fewer females (38.9%) than males (61.1%), and the mean EASI score of patients was 34.1. In the LIBERTY AD PEDS trial, the mean age of patients was 8.5 years, males and females were evenly balanced, and the mean EASI score of patients was ||||.

Efficacy Results

Key efficacy and safety results are summarized in Table 2.

For the primary efficacy end point, there was a larger proportion of patients in the dupilumab group who experienced an IGA score of 0 or 1 compared to the placebo group at week 16 with a between-treatment group difference of 23.8% (95% confidence interval [CI], 13.27% to 34.37%; P < 0.0001) in the LIBERTY AD PRESCHOOL trial. Results were similar in the LIBERTY AD PEDS trial with a larger proportion of patients in both dupilumab groups (every 4 weeks and every 2 weeks) who experienced an IGA score of 0 or 1 compared to the placebo group at week 16 with between-treatment group differences of 21.4% (95% CI, 11.36% to 31.45%; P < 0.0001) and 18.1% (95% CI, 8.28% to 27.97%; P < 0.0001), respectively.

In the LIBERTY AD PRESCHOOL trial, a larger proportion of patients in the dupilumab group experienced EASI-75 compared to the placebo group at week 16 with a between-treatment group difference of 42.3% (95% CI, 29.47% to 55.16%; P < 0.0001). Similarly, there was a larger percent change from baseline to week 16 EASI score observed in the dupilumab group compared to the placebo group, with a between-treatment group least squares mean (LSM) difference of –50.4% (95% CI, –62.38% to –38.40%; P < 0.0001). Results for the proportion of patients experiencing a 90% reduction in Eczema Area and Severity Index score (EASI-90) at week 16 also favoured treatment with dupilumab. In the LIBERTY AD PEDS trial, a larger proportion of patients in both dupilumab groups, every 4 weeks and every 2 weeks, experienced an EASI-75 score compared to the placebo group at week 16 with between-treatment group differences of 42.8% (95% CI, 31.54% to 54.15%; P < 0.0001) and 40.4% (95% CI, 28.95% to 51.82%; P < 0.0001), respectively. Likewise, there was a larger percent change from baseline to week 16 EASI score observed in both dupilumab groups, every 4 weeks and every 2 weeks, compared to the placebo group with between-group LSM differences of –33.4% (95% CI, ||||||| || |||||||; P < 0.0001) and –29.8% (95% CI, ||||||| || |||||||; P < 0.0001), respectively. Results for the proportion of patients experiencing EASI-90 at week 16 also favoured treatment with dupilumab.

In the LIBERTY AD PRESCHOOL trial, for the itch NRS score, a larger percent change from baseline to week 16 was observed in the dupilumab group compared to the placebo group with a between-group LSM difference of –47.1% (95% CI, –59.47% to –34.79%; P < 0.0001). Results for the proportion of patients experiencing an improvement of at least 4 points in itch NRS score from baseline to week 16 also favoured treatment with dupilumab. In the LIBERTY AD PEDS trial, a larger percent change from baseline to week 16 was observed for the itch NRS score in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group with between-group LSM differences versus placebo of –28.6% (95% CI, ||||||| || |||||||; P < 0.0001) and –31.0% (95% CI, ||||||| || |||||||; P < 0.0001), respectively. Results for the proportion of patients experiencing an improvement of at least 4 points in itch NRS score from baseline to week 16 also favoured treatment with dupilumab.

In the LIBERTY AD PRESCHOOL trial, a larger change from baseline to week 16 in the DFI score was observed in the dupilumab group compared to the placebo group with a between-group LSM difference of –7.80 (95% CI, –9.79 to –5.81; P < 0.0001). In the LIBERTY AD PEDS trial, a larger change from baseline to week 16 in the DFI score was observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group with between-group LSM differences versus placebo of –3.98 (95% CI, ||||| || |||||) and –4.11 (95% CI, ||||| || |||||), respectively.

In the LIBERTY AD PRESCHOOL trial, a larger change from baseline to week 16 in the CDLQI score was observed in the dupilumab group compared to the placebo group with a between-group LSM difference of –7.5 (95% CI, –10.29 to –4.75; P < 0.0001). In the LIBERTY AD PEDS trial, a larger change from baseline to week 16 in the CDLQI score was observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group with between-group LSM differences versus placebo of –4.2 (95% CI, ||||| || |||||; P < 0.0001) and –4.3 (95% CI, ||||| || |||||; P < 0.0001), respectively.

In the LIBERTY AD PRESCHOOL trial, a larger change from baseline to week 16 in the IDQOL score was observed in the dupilumab group compared to the placebo group with a between-group LSM difference of –8.96 (95% CI, –11.71 to –6.20; P < 0.0001). This was not an outcome in the LIBERTY AD PEDS trial.

Harms Results

During the 16-week treatment period, more than half of patients in any treatment group for either trial experienced at least 1 treatment-emergent adverse event (TEAE). In the LIBERTY AD PRESCHOOL trial, 63.9% of patients in the dupilumab group and 74.4% of patients in the placebo group reported a TEAE with the most frequently reported events being atopic dermatitis (13.3% dupilumab and 32.1% placebo), nasopharyngitis (8.4% dupilumab and 9.0% placebo), and upper respiratory tract infection (6.0% dupilumab and 7.7% placebo). In the LIBERTY AD PEDS trial, 65.0% of patients in the dupilumab every 4 weeks group, 67.2% of patients in the dupilumab every 2 weeks group, and 73.3% of patients in the placebo group reported a TEAE with the most frequently reported events also being nasopharyngitis (12.5% dupilumab every 4 weeks, 6.6% dupilumab every 2 weeks, and 6.7% placebo), upper respiratory tract infection (10.8% dupilumab every 4 weeks, 8.2% dupilumab every 2 weeks, and 10.0% placebo), and atopic dermatitis (6.7% dupilumab every 4 weeks, 8.2% dupilumab every 2 weeks, and 14.2% placebo).

In the LIBERTY AD PRESCHOOL trial, there were 4 serious adverse events (SAEs) reported in the placebo group and 0 in the dupilumab group. In the LIBERTY AD PEDS trial, there were 2 SAEs reported in the dupilumab every 4 weeks group, 0 in the dupilumab every 2 weeks group, and 2 in the placebo group. No SAE was reported by more than 1 patient per trial.

In the LIBERTY AD PRESCHOOL trial, 2 patients stopped treatment due to adverse events (AEs) due to atopic dermatitis (dupilumab group) and nightmare (placebo group). In the LIBERTY AD PEDS trial, 4 patients stopped treatment due to AEs: 2 due to food allergy and bacterial conjunctivitis (both patients were in the dupilumab every 2 weeks group) and 2 due to atopic dermatitis and asthma (both patients were in the placebo group).

There were no patient deaths in either trial.

Notable Harms

There were no reports of anaphylactic reaction in either trial.

There were no reports of hypersensitivity in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, no treatment-related events of hypersensitivity or anaphylaxis occurred during the study.

There were no reports of helminthic infection in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, | ||||||| || |||| of the dupilumab every 4 weeks and placebo groups reported a helminthic infection and || |||||||| in the dupilumab every 2 weeks group.

In the LIBERTY AD PRESCHOOL trial, 3 patients in the dupilumab group and 0 patients in the placebo group reported conjunctivitis. In the LIBERTY AD PEDS trial, 5 patients, 7 patients, and 3 patients in the dupilumab every 4 weeks, dupilumab every 2 weeks, and placebo groups, respectively, reported conjunctivitis.

In the LIBERTY AD PRESCHOOL trial, 2 patients in the dupilumab group and 0 patients in the placebo group reported blepharitis. In the LIBERTY AD PEDS trial, blepharitis was reported by | ||||||| and | |||||||| in the dupilumab every 2 weeks and placebo groups, respectively, and || |||||||| in the dupilumab every 4 weeks group.

In the LIBERTY AD PRESCHOOL trial, 1 patient in the dupilumab group and 0 patients in the placebo group reported keratitis. In the LIBERTY AD PEDS trial, | ||||||| in the dupilumab every 2 weeks group reported keratitis and || |||||||| in either the dupilumab every 4 weeks or placebo groups.

In the LIBERTY AD PRESCHOOL trial, 2 patients in the dupilumab group and 0 patients in the placebo group reported eosinophilia. In the LIBERTY AD PEDS trial, 1 patient in the dupilumab every 2 weeks group reported eosinophilia and no patients in either the dupilumab every 4 weeks or placebo groups.

Facial erythema was not captured in either trial.

Injection site pain was not captured in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, 3 patients, 2 patients, and 3 patients in the dupilumab every 4 weeks, dupilumab every 2 weeks, and placebo groups, respectively, reported injection site pain.

Table 2: Summary of Key Results From Pivotal Studies and RCT Evidence

AE = adverse event; CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; EASI-75 = 75% reduction in Eczema Area and Severity Index score; EASI-90 = 90% reduction in Eczema Area and Severity Index score; FAS = full analysis set; IDQOL = Infants’ Dermatitis Quality of Life Index; IGA = Investigator’s Global Assessment; LSM = least squares mean; NA = not applicable; NR = not reported; NRS = numeric rating scale; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RCT = randomized controlled trial; SAE = serious adverse event; SAS = safety analysis set; SD = standard deviation; SE = standard error; TCS = topical corticosteroid; TEAE = treatment-emergent adverse event.

^aP value has been adjusted for multiple testing.

^bP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to less than 15 kg, 15 kg to less than 30 kg). The stratum (Europe region, baseline weight less than 15 kg, IGA 3) was combined with the stratum (Europe region, baseline weight at least 15 kg, IGA 3) as the former had only 2 patients.

^cP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe) and baseline body mass (less than 30 kg, at least 30 kg).

^dThe CI and P value were based on treatment difference (dupilumab vs. placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to less than 15 kg, 15 kg to less than 30 kg) as fixed factors.

^eThe CI and P value were based on treatment difference (dupilumab vs. placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), and baseline body mass (less than 30 kg, at least 30 kg) as fixed factors.

^fN1 is the number of patients with baseline NRS score of at least 4.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Critical Appraisal

In both pivotal trials, the few differences in baseline patient characteristics were mostly small, could have been due to chance, and the clinical experts did not think they were likely to change treatment outcomes. In the LIBERTY AD PEDS trial, 68 patients may have been unblinded to their treatment assignment, but the trial enrolled additional patients and included a modified full analysis set (mFAS) for supportive analyses to mitigate the issue. In both trials, fewer patients in the dupilumab groups used rescue treatment compared to the placebo groups and the difference could impact how some outcomes (e.g., harms, HRQoL) are interpreted, though the direction of bias is not clear. Additionally, there was a lack of validity and reliability evidence for the itch NRS, and no minimal important differences (MIDs) for the IGA, DFI, or IDQOL scores for the patient population identified from the literature.

Although the LIBERTY AD PEDS trial included only patients with severe atopic dermatitis, the clinical experts were of the opinion that the results would likely be generalizable to those with moderate disease given the evidence for age groups both younger and older than that in the trial (i.e., aged 6 years to younger than 11 years). The experts suggested that, in practice, a patient with moderate atopic dermatitis and an EASI score less than 16 may be eligible for dupilumab if, for example, they have severe lesions, but low percent BSA affected or have lesions localized to special areas (e.g., hands, feet, scalp). This is supported by the literature showing that patients with moderate atopic dermatitis can have an EASI score as low as 6.^34,35 In the trials, patients who used rescue treatment were considered nonresponders, which the clinical experts stated was inconsistent with clinical practice. As per the clinical experts, non-TCS topical therapies would be acceptable add-on treatment while receiving dupilumab and a short course (< 8 weeks) of systemic therapies could be permitted without having to discontinue dupilumab. Although the trial outcomes addressed most of the treatment goals and patients’ needs from the stakeholder input, it is unclear if dupilumab injections every 2 weeks or every 4 weeks meet the need for a simpler treatment, particularly if patients or their caregivers are uncomfortable with administering the injection and the injections must be given in a clinic or if patients are especially afraid of needles.

Long-Term Extension Studies

Study 1434 is an ongoing, global, open-label, single-group, long-term extension (LTE) study of patients aged 6 months to younger than 18 years with atopic dermatitis with the aim to assess the long-term safety and efficacy of dupilumab.^38,39 Patients who participated in the parent (pivotal) trials were eligible to enrol in Study 1434; 180 patients were from the LIBERTY AD PRESCHOOL trial and 368 patients were from the LIBERTY AD PEDS trial. The primary outcome was the incidence rate (events per patient-year) of TEAEs. Results presented were based on a prespecified second-step analysis conducted on data from patients aged 6 years to younger than 12 years (data cut-off date July 22, 2019) and from a third-step analysis conducted on data from patients aged 6 months to younger than 6 years (data cut-off date July 31, 2021).

Efficacy Results

At the time of this CADTH review, Study 1434 was still ongoing and no patients had completed the 260-week assessment. However, early findings from baseline, 4, 16, 28, 52, and 104 weeks of primary and secondary efficacy end points indicated that treatment effects were maintained with continued dupilumab use.

Harms Results

No new safety signals arose during the course of the Study 1434 and early safety results indicated that the drug was generally well tolerated with an acceptable safety profile.

Critical Appraisal

The limited availability of long-term data (i.e., mature data), open-label design, lack of control arm, and absence of formal statistical hypothesis testing were key constraints that limit the interpretation of the long-term efficacy and safety of study outcomes for treatment with dupilumab.

Indirect Comparisons

No indirect evidence was available.

Studies Addressing Gaps in the Pivotal and RCT Evidence

PEDISTAD, an observational study, was submitted by the sponsor to address gaps in the RCT evidence comparing dupilumab to other systemic treatments, such as methotrexate or cyclosporine, for patients aged younger than 12 years with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical therapies or when those therapies are not medically advisable.³ PEDISTAD is an ongoing, international, longitudinal, 5-year, prospective study initiated on September 28, 2018, aiming to examine the impact of systemic treatments on disease severity, safety, and treatment discontinuation in this patient population. Patients were eligible to enrol if they were currently receiving systemic treatment for atopic dermatitis, UV therapy, immunosuppressants, or were currently on topical treatment and would be candidates for systemic treatment. All analyses were descriptive, with no comparisons performed between different systemic treatment cohorts.

Efficacy Results

Based on findings from a 2-year interim analysis in the sponsor’s Summary of Clinical Evidence, there appeared to be greater numerical improvements in the EASI total score, percent BSA affected by atopic dermatitis, Patient-Oriented Eczema Measure (POEM) score, and combined CDLQI or IDQOL score among the patients receiving dupilumab compared to methotrexate or cyclosporine.

Harms Results

Patients receiving dupilumab had a lower discontinuation rate and reported fewer AEs than those treated with methotrexate or cyclosporine.

Critical Appraisal

Based on the limited available data and how they were presented, it was not possible to determine if the treatment groups were adequately similar enough to be compared to 1 another. Additionally, available data were limited to the 2-year interim results, which prevent long-term conclusions from being drawn for any outcome. There was a potential increased risk of uncontrolled confounding and selection bias in the study, no formal comparison between study groups was considered, and there was no information regarding how many patients had been lost to follow-up, nor how many patients were censored. The study included a small number of patients living in Canada and it is unclear how representative the preliminary results are to the population of pediatric patients with atopic dermatitis living in Canada.

Conclusions

Currently dupilumab is available for patients aged 12 years and older with moderate-to-severe atopic dermatitis whose condition is not adequately controlled with prescription topical therapy or when those treatments are not advisable. There are few treatments available for patients who are aged 6 months to younger than 12 years and often these treatments, such as systemic immunosuppressants or phototherapy, are not recommended, used off-label, are inappropriate or inaccessible, and are therefore not preferred in this patient population. Evidence from 2 phase III trials demonstrated that dupilumab in combination with TCS was clinically significantly more effective at improving all disease-related symptoms, including itching, disease severity, and also significantly improving HRQoL compared to TCS alone during 16 weeks of treatment. The treatment effect of dupilumab was likely maintained, though conclusions of long-term efficacy and safety are limited by the number of patients with long-term data at this time and the lack of long-term comparative evidence. No direct or indirect evidence was available on comparative effectiveness of dupilumab versus any alternative therapies including systemic therapies (such as cyclosporine, methotrexate, azathioprine, mycophenolate mofetil), and the ongoing observational study could not fill the evidence gaps of dupilumab treatment efficacy and safety versus other drugs for atopic dermatitis. The indication for dupilumab notes that the drug would be for patients in whom topical prescription therapies are not advisable; however, whether such patients were enrolled and the efficacy of dupilumab in this patient population were unclear. Finally, the Health Canada–approved indication for dupilumab is for the treatment of patients aged 6 months and older with moderate-to-severe atopic dermatitis, though there is no evidence available for patients with moderate atopic dermatitis who are aged 6 years to 12 years, and the magnitude of treatment effect of dupilumab in this patient population is unknown due to lack of data.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of the use of dupilumab 200 mg single-use syringe (200 mg per 1.14 mL) and 300 mg single-use syringe (300 mg per 2 mL) for SC injection in the treatment of moderate-to-severe atopic dermatitis in patients aged 6 months to younger than 12 years whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

Atopic dermatitis is a chronic, relapsing, inflammatory skin condition characterized by intense itching, red and swollen skin, papules, excoriation, and serous exudation.^4,5 In pediatric patients, atopic dermatitis tends to present at different sites than in adult patients, such as the face, extensor extremities, and cheeks and lesions are more often associated with oozing.^4,6

Multiple factors, including genetic mutations, environmental triggers, immune dysregulation, and microbial imbalance, can contribute to the development of atopic dermatitis.^40-45 Environmental triggers activate type 2 immune response characterized by interleukin (IL)-4, IL-5, and IL-13 signalling and, in turn, result in an inflammatory reaction and itching.^41-43 Family history of atopic dermatitis can be a significant risk factor for the development of disease and onset in early infancy or childhood can persist into adulthood in severe cases.^46-48 Other risk factors include starting complementary food after the age of 6 months, skin problems in the first few months of life, and elevated blood eosinophils (defined as at least 5% of total leukocytes) at 4 weeks of age.^48,49 Males younger than 2 years are also at an increased risk of developing atopic dermatitis.⁵⁰

Though many children will outgrow the condition by the age of 6 years to 12 years, disease severity and a family history of asthma are factors significantly associated with disease that persists into later childhood.¹⁰ It is common for children with atopic dermatitis to develop other allergic disorders that share the same type 2 inflammatory response pathophysiology that underlies atopic dermatitis; this process is referred to as the “atopic march.”^4,8,51 The prevalence of these comorbidities is generally high and ranges from 12% to 38% for asthma and wheezing,^11-14,51 8% to 24% for food allergy,^11,12,51 and 31% to 58% for allergic rhinitis or conjunctivitis.^12,14 Greater severity of atopic dermatitis is associated with a higher prevalence of coexisting type 2 inflammatory diseases.⁵¹

It has been estimated that atopic dermatitis affects 15% to 20% of children globally.^7,8 In Canada, the lifetime prevalence of atopic dermatitis is up to 17% of the population and there is evidence to suggest that the prevalence has increased during the past 30 years.⁹

Pediatric patients with atopic dermatitis experience substantial symptom burden with frequent comorbidities and reduced HRQoL.^10-20 Patients can suffer from itchy lesions⁴ leading to serious infections and are at an increased risk of developing other atopic diseases,^11-14,21 attention-deficit/hyperactivity disorder, autism spectrum disorder,¹⁴ and suffer from social stigma and bullying.²² Pediatric patients with moderate-to-severe atopic dermatitis experience chronic and severe itch affecting daily functioning, HRQoL, sleep, mental health, and wellbeing.^{4,16,27,52-56}

There are no specific diagnostic tests for atopic dermatitis,^4,6 though the clinical experts noted that there are several diagnostic criteria used for research purposes.^57-59 The most commonly used instruments in clinical trials to measure severity are the IGA, EASI, Physician’s Global Assessment, BSA, and SCORAD.

The care required for pediatric patients with atopic dermatitis can be time-consuming and interferes with day-to-day activities,²² leading to increased caregiver feelings of anxiety, depression, worry, helplessness,²³ suboptimal sleep quality, and chronic exhaustion.^22,60 Additionally, atopic dermatitis management adds a substantial financial burden on the health care system and society,^24,25,27-30 and incurs indirect social and financial costs to patients and caregivers due to school²² and work absenteeism.²⁶

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

According to the clinical experts consulted by CADTH, the goals of treatment for pediatric patients with moderate-to-severe atopic dermatitis are to reduce symptom severity (e.g., itch, impact on sleep) and improve HRQoL with minimal adverse effects as well as reduce caregiver burden.

It is recommended that initial management of atopic dermatitis starts with education about the condition along with consistent, liberal use of emollients throughout the day.³² Management also includes identifying and avoiding triggers that cause disease flares (e.g., hypersensitivity reaction to topical therapies, low humidity environments, stress, irritants, allergens) and using dilute bleach baths and wet wraps containing low-to-medium-potency TCS, though the clinical experts indicated that the latter 2 are not used for most patients.³² The clinical experts consulted by CADTH stated that most patients with moderate-to-severe atopic dermatitis are managed with prescription topical anti-inflammatory treatments such as medium-to-high-potency TCSs and TCIs. The experts noted that topical crisaborole is less commonly used among these patients and is indicated for mild-to-moderate atopic dermatitis.⁶¹ Topical treatments can have adverse effects, are time-consuming for patients and their caregivers, tend to have low compliance, which can contribute to refractory disease, and not all patients respond to them.³² As per 1 clinical expert, TCIs are expensive and not always covered by insurance, limiting the available options.

The experts stated that pediatric patients with severe disease who do not respond to topical therapies, or in addition to topical therapies, may receive UV B phototherapy or off-label systemic immunosuppressants (e.g., cyclosporine, methotrexate, azathioprine, or mycophenolate mofetil), though these both have significant limitations.³² Phototherapy can be effective for some patients and does not carry the same risks as immunosuppressants; however, it is noted in the literature and by the clinical experts that patients must be independent enough to stand unattended for the session, phototherapy is associated with skin cancer (low risk), and it can be time-consuming requiring repeated weekly visits, which is not always practical for a chronic condition.³²

Although immunosuppressants can be used in pediatric patients with severe atopic dermatitis, the clinical experts expressed that their use is uncommon in patients aged younger than 5 years and rare in patients younger than 2 years. According to the literature, cyclosporine (3 mg/kg/day to 5 mg/kg/day in 2 divided doses) is given for 2 months to 4 months, after which it can be tapered over a number of months and discontinued once the patient improves and remains stable.³² Intermittent maintenance therapy may be necessary to prevent relapses.³² Methotrexate (0.5 mg/kg) is given once weekly to a maximum of 25 mg/week.³² Systemic corticosteroids are avoided in these patients but can be reserved for when there are no other available treatments, as a bridge to other treatments, for immediate treatment of acute flares, and for patients with very severe disease.³² Mycophenolate mofetil and azathioprine have been used to treat children with atopic dermatitis, but the evidence is very limited and of low quality.³² Systemic immunosuppressants can lead to an incomplete response in some patients and these drugs are not recommended for long-term use.³ Moreover, the clinicians stated that the drugs are associated with significant and intolerable adverse effects, such as cytopenia, increased risk of infection, hepatotoxicity, and renal damage and require regular bloodwork that is burdensome to patients.

Drug Under Review

Key characteristics of dupilumab are summarized in Table 3, along with other treatments available for moderate-to-severe atopic dermatitis.

Dupilumab is indicated for the treatment of patients aged 6 months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, and can be used with or without TCS.¹ For patients aged 6 months to 11 years, the drug is available as prefilled syringes containing either 200 mg (200 mg per 1.14 mL) or 300 mg (300 mg per 2 mL) dupilumab for SC injection with age and weight-based dosing.¹ According to the product monograph, patients aged 6 months to 5 years with atopic dermatitis who are 5 kg to less than 15 kg receive 200 mg every 4 weeks and those who are 15 kg to less than 30 kg receive 300 mg every 4 weeks.¹ Patients aged 6 years to 17 years with atopic dermatitis who are 15 kg to less than 30 kg initially receive 600 mg (two 300 mg injections) and then 300 mg every 4 weeks as maintenance, those who are 30 kg to less than 60 kg initially receive 400 mg (two 200 mg injections) and then 200 mg every 2 weeks as maintenance, and those 60 kg or greater initially receive 600 mg (two 300 mg injections) and then 300 mg every 2 weeks as maintenance.¹

Dupilumab is a recombinant human immunoglobulin G4 monoclonal antibody that inhibits IL-4 and IL-13 signalling, which is involved in type 2 inflammatory responses and atopic conditions.¹

Dupilumab underwent a standard review by Health Canada and was issued a Notice of Compliance on April 14, 2023.² Previously, dupilumab was reviewed by CADTH for the treatment of patients aged 12 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.³³ The CADTH Canadian Drug Expert Committee recommended that dupilumab be reimbursed with clinical criteria and/or conditions for patients aged 12 years and older with moderate-to-severe atopic dermatitis.³³ Currently, the sponsor has requested reimbursement be expanded to include the treatment of patients aged 6 months to younger than 12 years with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.²

Table 3: Key Characteristics of Dupilumab, Methotrexate, Cyclosporine, Azathioprine, and Mycophenolate Mofetil

IL = interleukin; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous; TCS = topical corticosteroid.

^aHealth Canada–approved indication.

Source: Product monographs for dupilumab, methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil.^1,62-65

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by 3 patient groups. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

Three patient groups responded to CADTH’s call for patient input: Eczema Society of Canada and a joint input from Canadian Skin Patient Alliance and Eczéma Québec. The inputs were provided for a previous CADTH submission for dupilumab in 2021, where the indication was for patients aged 6 years to 11 years with moderate-to-severe atopic dermatitis. No new input was received for the current review of dupilumab.

Eczema Society of Canada is a registered Canadian charity dedicated to improving the lives of Canadians living with eczema. Canadian Skin Patient Alliance is a national nonprofit organization dedicated to advocating, educating, and supporting Canadians living with diseases that affect skin, hair, and nails. Eczéma Québec is a patient advisory committee and registered nonprofit organization with the goal of building resources and establishing knowledge translation tools to improve education and raise awareness and health outcomes of patients with atopic dermatitis and health care practitioners. Eczema Society of Canada gathered information for this submission via written questionnaires, surveys, and interviews. Eczema Society of Canada survey data included 1,035 respondents providing their experience about the impact of atopic dermatitis on their quality of life and 299 respondents about systemic treatments for atopic dermatitis and reports on patient experience for those aged 17 years and younger. Canadian Skin Patient Alliance and Eczéma Québec collaborated to hold discussions and one-on-one interviews with patients with atopic dermatitis and caregivers by reaching them through social media platforms, newsletters, and emails.

Based on the input from the 3 patient groups, chronic itch and pain negatively affect individuals and their families, though the impact varies depending on disease severity. Eczema Society of Canada input indicated that 70% of survey respondents with moderate-to-severe atopic dermatitis suffer from interrupted sleep, with 18% having poor sleep for more than 14 nights per month. Survey results indicated that 69% of caregivers reported experiencing anxiety, 25% of them reported experiencing depression due to managing a child with atopic dermatitis, and 41% indicated they feel like a failure when they cannot control their child’s flares. Parents of children with atopic dermatitis reported feeling exhausted and helpless dealing with extra daily burdens.

According to the patient groups, itching is consistently rated as the most bothersome symptom resulting in uncontrollable scratching and damaged skin, which leads to children feeling embarrassment and shame due to visible blood stains, skin rash crusting, bleeding, and scabbing. Furthermore, periods of flares add more burden and contribute to missed school and activities, social isolation, bullying, psychosocial issues, an increased risk of mental health problems, and suicidal ideation. Additionally, the authors of the joint input stated that quality of life, access to care, and disease management are all areas of concern for patients and their caregivers and are associated with significant psychosocial, educational, financial, and occupational burdens. They indicated that comorbidities associated with pediatric atopic dermatitis, such as food allergies, asthma, allergic rhinoconjunctivitis, eosinophilic esophagitis, learning disabilities, and mental health issues, require multidisciplinary management and screening to address these problems, yet many patients reported not having been recommended for screening.

The patient groups indicated that for many living with atopic dermatitis, frequent moisturizing, trigger avoidance, and the use of topical treatments work well to control flares. For others with more severe symptoms, phototherapy and systemic therapies, including corticosteroids and off-label systemic immunosuppressants, which are not indicated for pediatric patients, are used to manage their disease. These treatments raised significant safety concerns among patients and caregivers, have limited long-term benefits, can result in rebound flares after stopping (e.g., corticosteroids), and can be challenging to access (e.g., phototherapy clinics). The authors of the joint input stated that the complex, time-consuming skin maintenance and treatment routines and other associated burdens make managing the disease very challenging and exhausting. According to the patient groups, there is a need for new treatment options that safely and effectively manage itch, redness, and inflammation, reduce flares, and improve HRQoL.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of moderate-to-severe atopic dermatitis.

Unmet Needs

The clinical experts consulted by CADTH explained that the currently available therapies have limitations that hinder effective management in pediatric patients with moderate-to-severe atopic dermatitis. They stated that not all patients respond to topical anti-inflammatory treatment, which 1 clinical expert stated was the safest option available for most patients. It was noted that topical treatments can be time-consuming and have low adherence, TCSs can have side effects, and TCIs are often expensive and not covered by insurance plans. The clinical experts stated that phototherapy is often not feasible for young children who must stand still and unattended in the phototherapy booth, it is associated with causing skin cancer (low risk), and requires repeated administration, but can only be used for a few months at a time, which is not ideal for treating a chronic disease. Lastly, the experts described the limitations with systemic immunosuppressants (e.g., methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil), including numerous adverse effects, poor tolerance resulting in an incomplete response, and regular blood monitoring requirements that are burdensome for patients. The clinical experts added that while systemic immunosuppressants are currently prescribed for pediatric patients with severe atopic dermatitis, they are seldomly used in those aged younger than 5 years and rarely used in those younger than 2 years.

Place in Therapy

Dupilumab targets the underlying disease process and, according to the clinical experts, would be used as a second-line therapy after failure of an adequate trial with topical therapies (e.g., TCS, TCI), but before systemic immunosuppressants due to their poor safety profile. Both experts believed that for pediatric patients aged younger than 12 years, it would be inappropriate to require treatment failure of either phototherapy or systemic immunosuppressants before becoming eligible for dupilumab. The clinicians expect dupilumab to be used with or without topical treatments.

Patient Population

One expert stated that misdiagnosing atopic dermatitis is unlikely, particularly in children. Both clinical experts indicated that patients suitable for treatment with dupilumab would be identified through clinician examination and judgment, taking into account disease severity and inadequate response to topical therapies. As per 1 of the experts, these patients would have an IGA score of 3 or 4, EASI score of 16 or greater, and have 10% or greater BSA affected; however, these assessment tools are not routinely used in clinical practice. The experts agreed that patients with severe atopic dermatitis, whose disease is refractory to topical therapies and has a major impact on their HRQoL, are most in need of effective treatment.

Assessing the Response to Treatment

One clinical expert stated that patients are usually assessed through a combination of verbal discussion with the patient and their caregivers about treatment response (e.g., symptom improvement, better HRQoL) as well as physical exam of the affected areas. It was suggested that there are likely small differences among physicians in assessments of response to treatment. The experts indicated that instruments used in clinical trials, such as the IGA, EASI, itch NRS, and CDLQI, can help to gauge treatment response but are not typically used in clinical practice, except when required by a health insurer. One clinician added that of the listed instruments, the IGA is a simple and somewhat reliable measure that can be used in a clinical setting. It was noted that patients receiving dupilumab can have a delayed response and that it would be reasonable to assess patients for response to treatment approximately 3 months to 6 months after initiating treatment with dupilumab then every 6 months thereafter.

Discontinuing Treatment

According to the experts, discontinuation of dupilumab should be considered if there is a lack of response to treatment (e.g., no improvement in rash, itch, or HRQoL) or there are intolerable adverse effects. One clinician added that patients often continue to use topical treatments alongside dupilumab, and it would not be a reason for discontinuing treatment. Severe conjunctivitis was noted as being a reason some patients may stop treatment temporarily or permanently; however, the experts indicated that adverse effects may be transient or mild, and patients often continue to receive treatment.

Although it is possible to outgrow childhood atopic dermatitis, both experts explained that it is less likely for patients with severe disease, with other atopic comorbidities, or with persistent and generalized atopic dermatitis, and these patients may require ongoing treatment. At this time, it is unclear if a pediatric patient who has been treated with dupilumab should stop the drug to assess sustained disease remission without it, nevertheless, the experts suggested that a trial of increasing the time between injections (e.g., every 6 weeks as opposed to every 4 weeks) once disease control is achieved with the plan to stop dupilumab altogether could be an option discussed and decided on between the treating physician, patient, and caregiver, though stopping the drug should not be forced.

Prescribing Considerations

It was suggested that dupilumab be initiated in a hospital or community clinical setting and both experts agreed that a specialist (i.e., dermatologist who has experience with the instruments [e.g., EASI] required to access dupilumab) would prescribe the drug. It was noted that there may be limited access to pediatric dermatologists and general dermatologists may hesitate to prescribe dupilumab in children. In those instances, the clinical experts suggested that a general pediatrician, allergist, immunologist, or a physician with training in atopic dermatitis could prescribe the drug. The experts stated that some pediatric patients do not tolerate injectable medications, but techniques can be used to reduce the pain and anxiety around treatment.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by 1 clinician group. The full original clinician group input received by CADTH has been included in the stakeholder section at the end of this report.

Clinician group input was provided by 1 group, the Canadian Dermatology Association, which advocates for continuing medical education for its members, supports patient care, and provides public education on several aspects of skin care.

According to the clinician group, the current treatment paradigm for atopic dermatitis in children aged 6 months to 11 years starts with education regarding general measures such as bathing practices and moisturizer use. The most common first-line therapies for atopic dermatitis are TCSs, TCIs, and topical phosphodiesterase type 4 inhibitors (e.g., crisaborole). Phototherapy or off-label systemic drugs such as short courses of prednisone and longer courses of methotrexate or cyclosporine are used occasionally.

The clinician group input provided insight into Eczema Society of Canada’s 2017 quality of life survey report for moderate-to-severe atopic dermatitis in children. According to this survey, issues include long wait times to access specialists and inadequate disease control among these patients. Furthermore, those with severe atopic dermatitis report failing topical steroids, moisturizers, oral antihistamines, TCIs, and even systemic steroids. Given the many different treatments and the regimented care involved with atopic dermatitis, caregivers find these treatments to be very challenging and described experiencing sleep loss, anxiety, stress, financial burden, and lack of support.

Eczema Society of Canada’s 2021 survey, also highlighted in the clinician group input, described how severe atopic dermatitis has a significant impact on children’s quality of life and affects their mood, school performance, and concentration. It was noted that there are many unavoidable external factors such as weather, stress, and exercise that can severely trigger itch and, in turn, affect patients’ quality of sleep.

The clinician group stated that an ideal treatment would have a proven safety record in this age group and would also be able to reduce itching and improve sleep, concentration at school, and the overall quality of life for both patients and caregivers.

It was stated in the input that recurrent courses of oral steroids for pediatric patients could lead to many short- and long-term adverse effects and that traditional systemic immunosuppressants, such as methotrexate and cyclosporine, are associated with a significant risk of cytopenias, multiorgan impairment (liver, renal), and increased risk of infection in young children. The clinician group also indicated that most dermatologists in Canada are not trained in, nor comfortable, managing pediatric safety laboratory tests in the context of systemic immunosuppression. According to the clinician group input, dupilumab is the only systemic treatment for atopic dermatitis indicated for this age group and does not carry the same profile risks as traditional immunosuppressants and thus, it is considered the treatment of choice for patients with moderate-to-severe disease requiring a systemic therapy.

The clinician group was of the opinion that any patient with moderate-to-severe atopic dermatitis who has experienced topical therapy failure with recurrent courses of oral steroids, and whose quality of life (and that of their caregiver) is significantly impacted, could potentially benefit from dupilumab. The group indicated that patients least suitable would include those with mild atopic dermatitis and those well-controlled with topical therapy.

According to the input, outcomes used in clinical practice to assess a clinically meaningful response would be measured at monthly intervals then every 4 months to 6 months and include a reduction in EASI scores and itching, improvements in skin appearance, quality of life, mental health, and outlook. As per the clinician group, factors to consider when deciding to discontinue therapy would include inability to achieve a clinically meaningful response 3 months to 4 months after initiating treatment or intolerance to dupilumab. The group stated that a dermatologist would be required to diagnose atopic dermatitis and prescribe dupilumab. It was also emphasized that systemic immunosuppressants (e.g., methotrexate, cyclosporine) should not be a prerequisite for dupilumab coverage in patients aged 6 months to 5 years due to the significant harms associated with their use and the limited number of pediatric dermatologists trained in managing pediatric immunosuppression.

The clinician group input highlighted remote Indigenous communities as being vulnerable groups in which individuals with poorly controlled atopic dermatitis tend to be at higher risk for chronic skin diseases and secondary infections due to environmental factors, low income, and the many barriers to accessing proper health care services and resources. The authors of the input suggested that dupilumab can be a better, straightforward option as a safe and efficacious treatment for children in these communities which can help control atopic dermatitis and decrease comorbid skin conditions associated with this disease.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

BSA = body surface area; CDEC = CADTH Canadian Drug Expert Committee; EASI = Eczema Area and Severity Index; EASI-75 = 75% reduction in the Eczema Area and Severity Index score; IGA = Investigator’s Global Assessment; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of dupilumab 200 mg (200 mg per 1.14 mL) and 300 mg (300 mg per 2 mL) single-use syringes for SC injection in the treatment of moderate-to-severe atopic dermatitis in patients aged 6 months to younger than 12 years whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The focus will be placed on comparing dupilumab to placebo and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of dupilumab is presented in 4 sections, and CADTH’s critical appraisal of the evidence is included after each section. The first section, the systematic review, includes 2 pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The second section includes 1 sponsor-submitted LTE study. The third section includes a feasibility assessment from the sponsor addressing the lack of indirect evidence. The fourth section includes an additional observational study that was considered by the sponsor to address important gaps in the pivotal and RCT evidence.

Included Studies

Clinical evidence from the following are included in the CADTH review and appraised in this document:

• 2 pivotal studies and RCT evidence

• 1 LTE study

• 1 feasibility assessment for conducting an indirect treatment comparison (ITC)

• 1 observational study to address gaps in the RCT evidence.

Pivotal Studies and RCT Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Description of Studies

Two phase III, DB, randomized, placebo-controlled trials (LIBERTY AD PRESCHOOL part B and LIBERTY AD PEDS) met the inclusion criteria for the sponsor’s systematic review. Characteristics of the LIBERTY AD PRESCHOOL part B and LIBERTY AD PEDS trials are summarized in Table 5 and the study designs are shown in Figure 1 and Figure 2, respectively.

The LIBERTY AD PRESCHOOL trial consisted of 2 parts. Part A (N = 40) was an open-label, single ascending dose, sequential cohort study investigating the pharmacokinetic, safety, and efficacy of a single dose of dupilumab in pediatric patients with severe atopic dermatitis (children aged 6 months to < 6 years). Data from part A were used to inform the dose regimen for part B, but results for the former are not presented in this CADTH review. Patients who enrolled in part A of the study were not eligible to participate in part B. Part B (N = 162; referred to as the LIBERTY AD PRESCHOOL trial in this report) was a double-blind RCT and its primary and secondary objectives were to investigate the efficacy and safety of dupilumab when administered concomitantly with TCS in patients aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. The LIBERTY AD PRESCHOOL trial consisted of 3 periods: an 8-week screening period (including 2 weeks of TCS standardization), 16-week treatment period, and 12-week follow-up period (for patients who did not enter the LTE). During the screening period, systemic treatments for atopic dermatitis were washed out, as applicable, according to the eligibility requirements and starting on day –14, all patients initiated a standardized low-potency TCS treatment regimen. Low-potency TCS was to be applied once daily to areas with active lesions. Once a patient experienced an IGA score of 2 or less, TCS frequency was to be decreased to 3 times per week, and then stopped once lesions were clear (IGA 0). If lesions returned, treatment with low-potency TCS was to be reinstituted with the same step-down approach. For lesions persisting or worsening under daily treatment with low-potency TCS, patients could be treated with medium-potency or high-potency TCS; super-potent or very high-potency steroids were not allowed even for rescue.

Patients who met the eligibility criteria underwent baseline assessments. Patients were randomized in a 1:1 ratio stratified by baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg), baseline disease severity (IGA 3, IGA 4), and region (North America, Europe, Japan, China). The number of patients with moderate atopic dermatitis (IGA 3) was capped at approximately 40 patients. Patients received 1 of the following treatment regimens: dupilumab every 4 weeks with TCS (body mass 5 kg to < 15 kg, 200 mg; body mass 15 kg to < 30 kg, 300 mg) or placebo with TCS. The primary outcome was the proportion of patients with an IGA score of either 0 or 1 at week 16. Patients were enrolled starting June 30, 2017, and the data cut-off date was September 16, 2021.

The LIBERTY AD PEDS trial (N = 367) was a double-blind RCT and its primary and secondary objectives were to demonstrate the efficacy and safety of dupilumab administered concomitantly with TCS in patients aged 6 years to younger than 12 years with severe atopic dermatitis. The study was conducted at 61 sites with 3 sites in Canada. The study consisted of 3 periods: an 11-week screening period (including 2 weeks of TCS standardization), 16-week treatment period, and 12-week follow-up (for patients who did not enter the LTE). TCS usage was standardized according to the following guidelines. Medium-potency TCS was applied once daily to areas with active lesions. Once a patient experienced an IGA score of 2 or less, the frequency of medium-potency TCS was reduced to 3 times per week and then stopped once lesions were clear (IGA 0). If lesions returned, treatment with medium-potency TCS was to be reinstituted with the same step-down approach. If there were signs of local or systemic TCS toxicity with medium-potency TCS, then patients were switched to low-potency steroids. For lesions persisting or worsening under daily treatment with medium-potency TCS, patients were treated with high-potency TCS; super-potent or very high-potency steroids were not allowed even for rescue.

Patients who met the eligibility criteria (N = 367) were randomized in a 1:1:1 ratio stratified by baseline body mass (< 30 kg, ≥ 30 kg) and region (North America, Europe) to dupilumab every 4 weeks with TCS (all patients regardless of body mass: 600 mg initial dose followed by 300 mg every 4 weeks), dupilumab every 2 weeks with TCS (body mass 15 kg to < 30 kg, 200 mg initial dose followed by 100 mg every 2 weeks; body mass ≥ 30 kg, 400 mg initial dose followed by 200 mg every 2 weeks), or matching placebo with TCS. The primary outcome was the proportion of patients with IGA 0 or 1 at week 16. Patients were enrolled starting November 17, 2017, and the data cut-off date was June 28, 2019.

In both trials, patients could enter a long-term safety study and receive open-label dupilumab.

Table 5: Details of Pivotal Studies Identified by the Sponsor

BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CGIC = Caregiver Global Impression of Change; CGID = Caregiver Global Impression of Disease; CNSQ = Caregiver-Reported Nasal Symptom Questionnaire; DB = double blind; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; EASI-50 = 50% reduction in Eczema Area and Severity Index score; EASI-75 = 75% reduction in Eczema Area and Severity Index score; EASI-90 = 90% reduction in Eczema Area and Severity Index score; GISS = Global Individual Signs Score; IDQOL = Infants’ Dermatitis Quality of Life Index; IFN = interferon gamma; IGA = Investigator’s Global Assessment; IgE = immunoglobulin E; LTE = long-term extension; NRS = numeric rating scale; PASQ = Pediatric Asthma Symptom Questionnaire; PGIC = Patient Global Impression of Change; PGID = Patient Global Impression of Disease; POEM = Patient-Oriented Eczema Measure; PROMIS = Patient-Reported Outcomes Measurement Information System; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RCT = randomized controlled trial; SAE = serious adverse event; SC = subcutaneous; SCORAD = Scoring Atopic Dermatitis; SCORAD-50 = 50% reduction in Scoring Atopic Dermatitis score from baseline; SCORAD-75 = 75% reduction in Scoring Atopic Dermatitis score from baseline; SCORAD-90 = 90% reduction in Scoring Atopic Dermatitis score from baseline; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid; TEAE = treatment-emergent adverse event; VAS = visual analogue scale.

Note: Two additional reports were included: Paller et al. and Paller et al.^66,67

^aInadequate response was defined as inability to achieve and/or maintain remission and low disease activity despite daily treatment with medium- to high-potency TCS (with or without TCI) used for at least 28 days. Patients who have received systemic atopic dermatitis treatment within 6 months before the trial were also considered inadequate responders to topical treatments.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Figure 1: Study Design for LIBERTY AD PRESCHOOL Trial

LTE = long-term extension; Std = standardization; TCS = topical corticosteroid.

Note: The length of the screening period, including TCS Std, was not fixed but did not exceed 56 days. The length of the TCS Std period was fixed at 14 days. Moisturizers were to be applied at least twice daily during the 7 consecutive days before randomization (not including the day of randomization) and were to be used throughout the trial. At least 11 of the 14 total applications of moisturizers before randomization must have been applied for the patient to remain eligible for the trial.

Source: LIBERTY AD PRESCHOOL Clinical Study Report.³⁷

Figure 2: Study Design for LIBERTY AD PEDS Trial

D = study day; LTE = long-term extension; OLE = open-label extension; TCS = topical corticosteroid; W = study week.

Note: The length of the screening period was not fixed, but the screening period and TCS standardization did not exceed 77 days. The length of the TCS standardization period was fixed at 14 days.

¹ For patients who entered the OLE, week 16 was the end of the trial.

Source: LIBERTY AD PEDS Clinical Study Report.³⁶

Populations

Inclusion and Exclusion Criteria

The LIBERTY AD PRESCHOOL trial included patients aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis that could not be adequately controlled with topical medications. At screening, patients must have had an IGA score of at least 3, EASI score of at least 16, and at least 10% BSA affected. Patient must have applied at least 11 out of 14 applications of a topical emollient during the 7 consecutive days before the baseline visit, and at least 11 out of 14 daily applications of low-potency TCS during the 2-week TCS standardization period leading up to the baseline visit. Patients were excluded if they had prior treatment with dupilumab, history of important side effects with low-potency TCS, or treatment with TCI or crisaborole within 2 weeks before baseline visit.

The LIBERTY AD PEDS trial included patients aged 6 years to younger than 12 years with severe atopic dermatitis that could not be adequately controlled with topical medications. At screening, patients must have had an IGA score of 4, EASI score of at least 21, and at least 15% BSA affected. Patients must have applied a stable dose of topical emollient twice daily during the 7 consecutive days before the baseline visit. Patients were excluded if they had prior treatment with dupilumab, history of important side effects with medium-potency TCS, or treatment with TCI or crisaborole within 2 weeks before baseline visit.

The key differences between the trials were the age groups and that the LIBERTY AD PEDS trial included patients with severe atopic dermatitis.

Interventions

In the LIBERTY AD PRESCHOOL trial, patients were randomized to either dupilumab every 4 weeks with TCS (fixed dose by body mass stratum of 200 mg every 4 weeks for patients 5 kg to < 15 kg; 300 mg every 4 weeks for patients 15 kg to < 30 kg) or matching placebo every 4 weeks with TCS. The assigned study drug was available in a single-use, prefilled glass syringe in doses of either 200 mg (175 mg per mL) or 300 mg (150 mg per mL) and was administered by SC injection by the investigator. Low-potency TCS treatment included hydrocortisone acetate 1% cream; if there was known hypersensitivity to hydrocortisone 1% or hydrocortisone acetate 1% cream or if neither was available, alclometasone dipropionate 0.05% cream or desonide 0.05% cream could be used.

In the LIBERTY AD PEDS trial, patients were randomized to dupilumab every 2 weeks with TCS (body mass-tiered dosing of 100 mg every 2 weeks with 200 mg initial dose for patients 15 kg to < 30 kg; 200 mg every 2 weeks with 400 mg initial dose for patients ≥ 30 kg), dupilumab every 4 weeks with TCS (300 mg every 4 weeks with 600 mg initial dose regardless of body mass), or matching placebo with TCS. Dupilumab was available in the same formats as described in the LIBERTY AD PRESCHOOL trial. Patients and caregivers could be trained to prepare and administer the study drug outside the study site during weeks in which no in-clinic visit was scheduled (for patients receiving treatment every 2 weeks) or they could have clinic staff administer the study drug in the clinic. Low-potency TCS treatment included hydrocortisone acetate 1% cream and medium-potency TCS treatment included triamcinolone acetonide 0.1% cream, fluocinolone acetonide 0.025% cream, or clobetasone butyrate 0.05%.

Rescue treatment for worsening atopic dermatitis was permitted at the discretion of the investigator and only after day 14 of the trial. Investigators were required to perform an IGA assessment before starting rescue treatment and initiate it only in patients who either had an IGA score of 4 or had intolerable symptoms. Efficacy and safety assessments were to be conducted before rescue treatment was administered. For the efficacy responder analysis, rescue treatment use was adjudicated by a blinded committee and patients who received rescue treatment were considered treatment failures. Investigators were encouraged to consider initial rescue with topical treatment and to escalate to systemic medications only for patients who did not respond adequately after at least 7 days of topical treatment. For the LIBERTY AD PRESCHOOL trial, rescue treatment included the medium-potency steroids triamcinolone acetonide 0.1% ointment, triamcinolone acetonide 0.1% cream, fluticasone propionate 0.05% cream, or fluocinolone acetonide 0.025% ointment and high-potency steroids mometasone furoate 0.1% ointment or triamcinolone acetonide 0.5% ointment. TCIs and crisaborole could also be used for rescue. For the LIBERTY AD PEDS trial, rescue treatment with high-potency steroids included mometasone furoate 0.1% ointment. Very high-potency steroids were prohibited in both trials. Patients could continue study treatment if rescue consisted of topical medications, but those who received systemic corticosteroids or systemic nonsteroid immunosuppressive drugs were discontinued permanently from the study drug.

Outcomes

A list of efficacy end points assessed in this clinical review report are provided in Table 6 and are further described in Table 7. Summarized end points are based on those included in the sponsor’s Summary of Clinical Evidence as well as any identified as important to this review according to stakeholders, for example the clinical experts, clinician groups, or patient group.

Table 6: Outcomes Summarized From Pivotal Studies Identified by the Sponsor

BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; EASI-50 = 50% reduction in Eczema Area and Severity Index score; EASI-75 = 75% reduction in Eczema Area and Severity Index score; EASI-90 = 90% reduction in Eczema Area and Severity Index score; IDQOL = Infants’ Dermatitis Quality of Life Index; IGA = Investigator’s Global Assessment; NA = not applicable; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; SCORAD = Scoring Atopic Dermatitis.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

Source: LIBERTY AD PRESCHOOL Clinical Study Report and LIBERTY AD PEDS Clinical Study Report.^36,37

Table 7: Summary of Outcome Measures and Their Measurement Properties

ANOVA = analysis of variance; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; IDQOL = Infants’ Dermatitis Quality of Life Index; IGA = Investigator’s Global Assessment; MID = minimal important difference; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation.

Incidence and seriousness of AEs, withdrawals due to AEs, and deaths were reported for the safety analysis set during the trials. AEs, SAEs, and protocol-defined notable harms were described based on preferred term and associated system organ class. Notable harms included those that were prespecified by the sponsor and confirmed by the clinical experts consulted by CADTH, such as anaphylactic reactions, hypersensitivity, helminthic infections, conjunctivitis, blepharitis, keratitis, eosinophilia, facial erythema, and pain with administration.

Statistical Analysis

Details of the statistical analysis of efficacy end points are summarized in Table 8.

Sample Size and Power Calculation

For the LIBERTY AD PRESCHOOL trial, it was estimated that a sample size of 160 patients (80 patients per treatment group), at the 2-sided 5% significance level using Fisher exact test, would provide an 88% power to detect a treatment difference of 21.4% between the dupilumab and placebo groups in the percentage of patients who experience an IGA score of 0 to 1 at week 16 and a 99% power to detect a treatment difference of 42.9% in the percentage of patients who experience an EASI-75 response at week 16. The assumptions used for the above power calculations were based on results from patients in the LIBERTY AD PEDS study.

Table 8: Statistical Analysis of Efficacy End Points From Pivotal Studies Identified by the Sponsor

ANCOVA = analysis of covariance; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CMH = Cochran-Mantel-Haenszel; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; EASI-50 = 50% reduction in Eczema Area and Severity Index score; EASI-75 = 75% reduction in Eczema Area and Severity Index score; EASI-90 = 90% reduction in Eczema Area and Severity Index score; IDQOL = Infants’ Dermatitis Quality of Life Index; IGA = Investigator’s Global Assessment; LOCF = last observation carried forward; mFAS = modified full analysis set; MI = multiple imputation; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; PP = per protocol; SCORAD = Scoring Atopic Dermatitis; WOCF = worst observation carried forward.

^aDue to the small number of patients, those in the Europe region, baseline body mass < 15 kg, and IGA 3 stratum were combined with those in the Europe region, baseline body mass ≥ 15 kg, and IGA 3 stratum.

^bRandomization strata included baseline body mass group (LIBERTY AD PRESCHOOL: 5 kg to < 15 kg, 15 kg to < 30 kg; LIBERTY AD PEDS: < 30 kg, ≥ 30 kg), disease severity (IGA 3, IGA 4), and region (North America, Europe).

^cPatients with missing data due to patient withdrawal (consent, AE, lack of efficacy), use of rescue treatment, or missing data at week 16 were considered nonresponders.

^dPatients with missing data due to other reasons were imputed using MI methods. MI methods involved data being imputed 40 times to generate 40 complete datasets. The monotone missing pattern was induced by Markov chain Monte Carlo method. After the first missing visit, subsequent missing data were imputed using the regression method for continuous variables and using the logistic regression method for categorical variables.

^ePatients with missing data due to patient withdrawal (consent, AE, lack of efficacy) or use of rescue treatment were imputed using WOCF methods.

^fPatients with missing data due to use of rescue medication were imputed using MI methods.

Source: LIBERTY AD PRESCHOOL Clinical Study Report and LIBERTY AD PEDS Clinical Study Report.^36,37

At the time the LIBERTY AD PEDS trial was designed, there were no data available on the effects of dupilumab in pediatric patients. The assumptions used for the power calculations were estimated based on results from the R668-AD-1224 study (phase III combination study with TCS for adults with atopic dermatitis) and R668-AD-1021 study (a phase IIb dose ranging study in adults with atopic dermatitis) for patients with an IGA score of 4 at baseline. For the primary outcome (IGA 0 or 1), it was initially estimated that with 80 patients per group, at the 2-sided 5% significance level, would provide 97% power to detect a 23% treatment difference between the dupilumab every 2 weeks and placebo groups and would provide 87% power to detect a 17% treatment difference between the dupilumab every 4 weeks and placebo groups. For the key secondary outcome of EASI-75 at week 16, 80 patients per group would provide 99% power to detect a 51% treatment difference between the dupilumab every 2 weeks and placebo groups and would provide 99% power to detect a 45% treatment difference between the dupilumab every 4 weeks and placebo groups.

Due to an inadvertent operational error, 68 patients were potentially unblinded (30 patients in the every 2 weeks group and 19 patients in each of the every 4 weeks and placebo groups) in the LIBERTY AD PEDS trial. These patients were excluded from the mFAS (supportive analyses). Additional patients were enrolled in the study to maintain study balance and power and to ensure that the original number of blinded patients for all treatment groups was available for sensitivity analyses that excluded the potentially unblinded patients.

Statistical Testing and Data Imputation Methods

In both trials, the proportion of patients with an IGA score of 0 or 1 at week 16 was the primary end point and the proportion of patients with EASI-75 at week 16 was a key secondary end point for the US and its reference markets. For Europe and European reference markets, the IGA and EASI-75 outcomes were co-primary end points.

In the LIBERTY AD PRESCHOOL trial, primary and secondary end points were analyzed using the full analysis set (FAS). The primary outcome of percentage of patients with an IGA score of 0 or 1 at week 16 used the Cochran-Mantel-Haenszel test adjusted by randomization strata (baseline body mass group [5 kg to < 15 kg, 15 kg to < 30 kg], baseline disease severity [IGA 3, IGA 4], and region [North America, Europe]). Similar procedures were used for the key secondary outcome of percentage of patients with EASI-75 at week 16. If a patient withdrew from the study or discontinued due to an AE or lack of efficacy, the patient was considered a nonresponder for the time points after withdrawal. If a patient used a rescue treatment, the patient was considered a nonresponder from when the rescue treatment was used. If the patient had the value missing at week 16 due to any other reasons, the data were imputed using multiple imputation based on all observed values. The underlying continuous (e.g., EASI) or categorical variables (e.g., IGA) were imputed 40 times to generate 40 complete datasets. Multiple imputation using the monotone missing pattern was induced by Markov chain Monte Carlo method in a multiple imputation procedure using seed number 12345. The missing data at subsequent visits were imputed using the regression method for the monotone pattern with seed number 54321 with adjustment for covariates including treatment groups, randomization strata, and relevant baseline variables. For the categorical variable, a logistic regression under monotone option was used. Binary secondary efficacy end points were analyzed using the same approaches used for the analysis of the primary end point. Continuous end points (e.g., EASI, worst itch NRS score) were analyzed using an analysis of covariance (ANCOVA) model with treatment, randomization strata, baseline disease severity, region, and relevant baseline values included in the model as the primary analysis method. Missing data for continuous end points were imputed by the pattern-mixture approach (multiple imputation-worst observation carried forward [WOCF] method). The WOCF approach was used for data after rescue or missing due to withdrawn consent, AE, and lack of efficacy. Missing data were imputed by postbaseline WOCF if there was at least 1 nonmissing postbaseline value or by baseline value if there was no postbaseline value. The multiple imputation approach was used for missing data due to other reasons as described for the primary end point.

In the LIBERTY AD PEDS trial, primary and secondary end points were analyzed using the FAS. The primary outcome of percentage of patients with an IGA score of 0 or 1 at week 16 and key secondary outcome of percentage of patients with EASI-75 at week 16 used the Cochran-Mantel-Haenszel test adjusted by randomization strata. A patient was considered a nonresponder if they withdrew from the study, used a rescue treatment, or had a missing value at week 16. All binary and continuous secondary end points were analyzed using the same approaches as outlined for the LIBERTY AD PRESCHOOL trial. The ANCOVA model used treatment, randomization strata, and relevant baseline variable as covariates.

Multiple Testing Procedure

A hierarchical procedure was used to control the overall type I error rate at 0.05 for the primary and secondary end points of dupilumab versus placebo. Each hypothesis was formally tested only if the preceding test was significant at the 2-sided 0.05 significance level. The hierarchical testing order for the 2 trials is summarized in Table 9.

Table 9: Hierarchical Testing in Pivotal Studies Identified by the Sponsor

BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; EASI-50 = 50% reduction in Eczema Area and Severity Index score; EASI-75 = 75% reduction in Eczema Area and Severity Index score; EASI-90 = 90% reduction in Eczema Area and Severity Index score; IDQOL = Infants’ Dermatitis Quality of Life Index; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; vs. = versus.

Source: LIBERTY AD PRESCHOOL Clinical Study Report and LIBERTY AD PEDS Clinical Study Report.^36,37

Subgroup Analyses

In the LIBERTY AD PRESCHOOL trial, prespecified subgroups for the primary and key secondary end points were analyzed based on the FAS. These included: age group, sex, ethnicity, race, duration of atopic dermatitis, body mass index, body mass group, age of disease onset, family history of atopic disease, region, baseline EASI, baseline worst itch, percent BSA, baseline SCORAD, previous use of cyclosporine, previous use of systemic immunosuppressants (systemic corticosteroids and systemic nonsteroidal immunosuppressant for atopic dermatitis), history of asthma, history of allergic rhinitis, and history of food allergies. Primary and secondary end points were analyzed in a similar manner as the main analysis for the severe atopic dermatitis subgroup (IGA 4) and nominal P values were provided. The sponsor noted that subgroup analyses for age group, ethnicity, duration of atopic dermatitis, baseline SCORAD score, and previous usage of cyclosporine were not conducted because subgroups were too small for meaningful conclusions to be drawn.

In the LIBERTY AD PEDS trial, prespecified subgroups for the primary and key secondary end points were analyzed based on the FAS. These included: age group, sex, ethnicity, race, duration of atopic dermatitis, age of disease onset, family history of atopic disease, baseline body mass group, body mass index, region, baseline severe or moderate-to-severe EASI, baseline worst itch, percent BSA, baseline SCORAD, previous use of cyclosporine, previous use of methotrexate, previous use of azathioprine, previous use of systemic immunosuppressants for atopic dermatitis, history of asthma, history of nasal polyps, history of allergic rhinitis, and history of food allergies. Subgroup analyses were analyzed in a similar manner as the main analysis. Interactions between the subgroups and treatment groups were tested using the logistic regression model for the categorical end points and using the ANCOVA model for the continuous end points. The model included randomization strata, treatment group, subgroup, treatment by randomization strata interaction, and treatment by subgroup interaction as factors. P values for the interaction term were reported and interaction effects were considered as significant if the P value was greater than 0.1. The sponsor noted that subgroup analyses for Hispanic or Latino patients, duration of atopic dermatitis of less than 5 years, patients aged 5 years or older at onset of atopic dermatitis, baseline EASI score of less than 25, baseline EASI score of less than 20, BSA of 10% to 30%, SCORAD score of less than 50, previous use of methotrexate for atopic dermatitis, previous use of azathioprine, and history of nasal polyps were too small for meaningful conclusions to be drawn.

The sponsor’s systematic review protocol listed 4 subgroups of interest: disease severity (e.g., moderate, severe), number of previous topical prescription therapies, previous immunosuppressant treatment (yes, no), and age (6 months to < 6 years, 6 years to < 12 years).

Sensitivity Analyses

In the LIBERTY AD PRESCHOOL trial, a sensitivity analysis on the co-primary end points was planned using the tipping point analysis method to assess the robustness of primary analysis results, but was not conducted because multiple imputation methods were implemented for only 1 patient.

In the LIBERTY AD PEDS trial, 2 sensitivity analyses were planned and used the FAS. In the first analysis, a postbaseline last observation carried forward approach after censoring for rescue treatment use or study withdrawal to determine a patient’s status at week 16 assessed the robustness of the primary efficacy analysis with regards to handling of missing data. In the second, all observed data were included for analysis, regardless of if rescue treatment was used or data were collected after withdrawal from study treatment. Patients with missing values were counted as nonresponders. Additional sensitivity analyses with the mFAS (due to potential unblinding of 68 patients) and per-protocol populations were used to analyze the primary and key secondary (i.e., IGA and EASI-75) end points.

Analysis Populations

Descriptions of the analysis populations used in the pivotal trials are summarized in Table 10.

Table 10: Analysis Populations of Pivotal Studies Identified by the Sponsor

FAS = full analysis set; mFAS = modified full analysis set; PP = per protocol; SAS = safety analysis set.

Source: Sponsor’s Summary of Clinical Evidence.³ (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Results

Patient Disposition

Patient disposition is summarized in Table 11.

In the LIBERTY AD PRESCHOOL trial, 197 individuals were screened, of which 162 patients met the eligibility criteria and were randomized to either the dupilumab or placebo group. One patient in the placebo group was randomized in error but did not receive study drug and was not included in the safety analysis set. In total, 83 (100%) patients in the dupilumab group and 76 (96.2%) patients in the placebo group completed the week 16 end-of-treatment visit. Three patients discontinued the study before week 16 and were from the placebo group.

In the LIBERTY AD PEDS trial, 474 individuals were screened, of which 367 patients met the eligibility criteria and were randomized into 1 of 3 treatment groups. Five of the randomized patients were not treated (3 patients in the combined dupilumab group and 2 patients in the placebo group) and were included in the FAS. In total, 237 (97.1%) patients in the combined dupilumab group and 114 (92.7%) patients in the placebo group completed treatment. Thirteen patients discontinued the study (7 patients in the combined dupilumab group and 6 patients in the placebo group) and reasons were balanced across treatment groups.

Table 11: Summary of Patient Disposition From Pivotal Studies

FAS = full analysis set; mFAS = modified full analysis set; NA = not applicable; PP = per protocol; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SAS = safety analysis set; TCS = topical corticosteroid.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Baseline Characteristics

Baseline patient characteristics and medical history are summarized in Table 12. The baseline characteristics outlined in the table are limited to those that are most relevant to this review or were likely to impact the outcomes or interpretation of the study results.

Overall, most characteristics were balanced among treatment groups in either trial. In the LIBERTY AD PRESCHOOL trial, the mean age of patients was 3.8 years, there were fewer females (38.9%) than males (61.1%), and the mean EASI score of patients was 34.1. In the LIBERTY AD PEDS trial, the mean age of patients was 8.5 years, males and females were evenly balanced, and the mean EASI score of patients was ||||. There was an imbalance in race between the dupilumab and placebo groups, and more patients in the placebo group had previously received methotrexate, while more patients in the dupilumab group had previously received systemic corticosteroids for atopic dermatitis.

Table 12: Summary of Baseline Characteristics From Pivotal Studies

BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DFI = Dermatitis Family Impact; EASI = Eczema Area and Severity Index; FAS = full analysis set; IDQOL = Infants’ Dermatitis Quality of Life Index; IGA = Investigator’s Global Assessment; max = maximum; min = minimum; NA = not applicable; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SAS = safety analysis set; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; TCS = topical corticosteroid.

Source: Sponsor’s Summary of Clinical Evidence.³ (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Exposure to Study Treatments

Exposure to study treatments is summarized in Table 13.

The duration of exposure to study drug was similar among treatment groups as was adherence to injections. Adherence to emollient use was lower than injection adherence and was lower in the LIBERTY AD PRESCHOOL trial compared to the LIBERTY AD PEDS trial. Also, in both trials, more patients who received placebo used at least 1 rescue medication compared to patients who received dupilumab with the most common being TCSs and rare use of systemic corticosteroids or noncorticosteroids. Note that the placebo group in the LIBERTY AD PEDS trial consisted of patients who received placebo every 4 weeks and patients who received placebo every 2 weeks in a 1:1 ratio explaining the mean and larger standard deviation (SD) compared to either dupilumab group.

Table 13: Summary of Patient Exposure From Pivotal Studies — SAS

FAS = full analysis set; max = maximum; min = minimum; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SAS = safety analysis set; SD = standard deviation; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid.

^aAnalyzed using the FAS.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Protocol Deviations

Protocol deviations are summarized in Table 14.

Most patients in either trial had at least 1 protocol deviation and less than 15% of patients had a deviation that was considered important or major. In the LIBERTY AD PRESCHOOL trial, the most common deviation was for receiving a prohibited treatment, whereas for the LIBERTY AD PEDS trial, the most common reason was patients entering the study despite entry criteria not being satisfied.

Table 14: Summary of Protocol Deviations From Pivotal Studies — FAS

AESI = adverse event of special interest; FAS = full analysis set; NA = not applicable; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; TCS = topical corticosteroid.

^aIn LIBERTY AD PRESCHOOL, 1 patient in had 5 deviations of “procedure not performed” (TCS dispensation not performed at 2 visits, TCS accountability not performed and vital signs not collected at 2 visits), 1 patient had 2 deviations of “procedure not performed” (TCS dispensation not performed, TCS accountability not performed), and 1 deviation of “visit performed out of window.” Another patient had a deviation of “visit performed out of window” and 2 patients had deviations of “visit not performed” (information from datasets). The case of inadequate informed consent was for a patient who became 4 years old at the end-of-treatment visit and therefore should have signed the assent form. However, the assent form was not signed before rolling over to the long-term extension study. Among the patients who received excluded concomitant treatment, 1 received a concomitant live (attenuated) measles, mumps, and rubella vaccine, and 2 received measles, mumps, and rubella and varicella vaccines.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Efficacy

IGA — Primary Outcome

Results for the IGA are summarized in Table 15.

In the LIBERTY AD PRESCHOOL trial, there was a larger proportion of patients in the dupilumab group who experienced an IGA score of 0 or 1 compared to the placebo group at week 16; the treatment difference was 23.8% (95% CI, 13.27% to 34.37%; P < 0.0001). Results from posthoc sensitivity analyses and prespecified subgroup analyses were consistent with the primary analysis.

In the LIBERTY AD PEDS trial, there was a larger proportion of patients in both the dupilumab every 4 weeks and every 2 weeks groups who experienced an IGA score of 0 or 1 compared to the placebo group at week 16; the treatment differences versus placebo were 21.4% (95% CI, 11.36% to 31.45%; P < 0.0001) and 18.1% (95% CI, 8.28% to 27.97%; P < 0.0001), respectively. Results from sensitivity analyses and prespecified subgroup analyses were consistent with the primary analysis.

Table 15: Summary of IGA Results From Pivotal Studies — FAS

CI = confidence interval; FAS = full analysis set; IGA = Investigator’s Global Assessment; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; TCS = topical corticosteroid.

^aP value has been adjusted for multiple testing.

^bP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg). Two strata were combined (Europe region, baseline body mass < 15 kg, and IGA 3 with Europe region, baseline body mass ≥ 15 kg, and IGA 3) as 1 of the strata had only 2 patients.

^cP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe) and baseline body mass (< 30 kg, ≥ 30 kg).

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

EASI — Secondary Outcomes

Results for the EASI are summarized in Table 16.

In the LIBERTY AD PRESCHOOL trial, there was a larger proportion of patients in the dupilumab group who experienced EASI-75 compared to the placebo group at week 16; the treatment difference was 42.3% (95% CI, 29.47% to 55.16%; P < 0.0001). Similarly, there was a larger percent change from baseline to week 16 EASI score observed in the dupilumab group compared to the placebo group; the LSM difference was –50.4% (95% CI, –62.38% to –38.40%; P < 0.0001). Results for the proportion of patients experiencing a 50% reduction in Eczema Area and Severity Index score (EASI-50) and EASI-90 at week 16 also favoured treatment with dupilumab. For EASI-75 and percent change from baseline to week 16 in EASI score outcomes, results from posthoc sensitivity analyses and prespecified subgroup analyses were consistent with the primary analysis.

In the LIBERTY AD PEDS trial, there was a larger proportion of patients in both the dupilumab every 4 weeks and every 2 weeks groups who experienced EASI-75 compared to the placebo group at week 16; the treatment differences versus placebo were 42.8% (95% CI, 31.54% to 54.15%; P < 0.0001) and 40.4% (95% CI, 28.95% to 51.82%; P < 0.0001), respectively. Likewise, there was a larger percent change from baseline to week 16 in EASI score observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo were –33.4% (95% CI, –40.06% to –26.82%; P < 0.0001) and –29.8% (95% CI, –36.33% to –23.24%; P < 0.0001), respectively. Results for the proportion of patients experiencing EASI-50 and EASI-90 at week 16 also favoured treatment with dupilumab. For EASI-75 and percent change from baseline to week 16 in EASI score outcomes, results from sensitivity analyses and prespecified subgroup analyses were consistent with the primary analysis.

Itch NRS Score — Secondary Outcomes

Results for the itch NRS are summarized in Table 17.

In the LIBERTY AD PRESCHOOL trial, there was a larger percent change from baseline to week 16 in the itch NRS score observed in the dupilumab group compared to the placebo group; the LSM difference was –47.1% (95% CI, –59.47% to –34.79%; P < 0.0001). Results for the proportion of patients experiencing an improvement of at least 3 points and at least 4 points in itch NRS score from baseline to week 16 also favoured treatment with dupilumab. For the percent change from baseline to week 16 in the itch NRS score outcome, results from post hoc sensitivity analyses and prespecified subgroup analyses were consistent with the primary analysis.

In the LIBERTY AD PEDS trial, there was a larger percent change from baseline to week 16 in the itch NRS score observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo were –28.6% (95% CI, –36.47% to –20.82%; P < 0.0001) and –31.0% (95% CI, –38.76% to –23.26%; P < 0.0001), respectively. Results for the proportion of patients experiencing an improvement of at least 3 points and at least 4 points in the itch NRS score from baseline to week 16 also favoured treatment with dupilumab. For the percent change from baseline to week 16 in the itch NRS score outcome, results from sensitivity analyses and prespecified subgroup analyses were consistent with the primary analysis.

Percent BSA Affected by Atopic Dermatitis — Secondary Outcome

Results for the percent BSA affected by atopic dermatitis are summarized in Table 18.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 for percent BSA affected by atopic dermatitis observed in the dupilumab group compared to the placebo group; the LSM difference was –24.27% (95% CI, –31.20% to –17.33%; P < 0.0001).

In the LIBERTY AD PEDS trial, there was a larger change from baseline to week 16 for percent BSA affected by atopic dermatitis observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo were –18.88% |||| ||| ||||||| || |||||||) and –17.72% |||| ||| ||||||| || |||||||), respectively.

POEM — Secondary Outcome

Results for the POEM are summarized in Table 18.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 in POEM score observed in the dupilumab group compared to the placebo group; the LSM difference was –9.1 (95% CI, –11.26 to –6.89; P < 0.0001).

In the LIBERTY AD PEDS trial, there was a larger change from baseline to week 16 in POEM score observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo were –8.3 |||| ||| |||||| || |||||| | | ||||||| and –8.1 |||| ||| ||||| || |||||| | | |||||||, respectively.

Table 16: Summary of EASI Results From Pivotal Studies — FAS

CI = confidence interval; EASI = Eczema Area and Severity Index; EASI-50 = 50% reduction in Eczema Area and Severity Index score; EASI-75 = 75% reduction in Eczema Area and Severity Index score; EASI-90 = 90% reduction in Eczema Area and Severity Index score; FAS = full analysis set; LSM = least squares mean; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SD = standard deviation; SE = standard error; TCS = topical corticosteroid.

^aP value has been adjusted for multiple testing.

^bP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg). Two strata were combined (Europe region, baseline body mass < 15 kg, and IGA 3 with Europe region, baseline body mass ≥ 15 kg, and IGA 3) as 1 of the strata had only 2 patients.

^cP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe) and baseline body mass (< 30 kg, ≥ 30 kg).

^dThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg) as fixed factors.

^eThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), and baseline body mass (< 30 kg, ≥ 30 kg) as fixed factors.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Table 17: Summary of Itch NRS Results From Pivotal Studies — FAS

CI = confidence interval; FAS = full analysis set; LSM = least squares mean; NRS = numeric rating scale; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SD = standard deviation; SE = standard error; TCS = topical corticosteroid.

^aThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg) as fixed factors.

^bThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe) and baseline body mass (< 30 kg, ≥ 30 kg) as fixed factors.

^cP value has been adjusted for multiple testing.

^dN1 is the number of patients with baseline NRS score of at least 4.

^eP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg). Two strata were combined (Europe region, baseline body mass < 15 kg, and IGA 3 with Europe region, baseline body mass ≥ 15 kg, and IGA 3) as 1 of the strata had only 2 patients.

^fP values were derived by Cochran-Mantel-Haenszel test stratified by region (North America, Europe) and baseline body mass (< 30 kg, ≥ 30 kg).

^gN1 is the number of patients with baseline NRS score of at least 3.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37(Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

SCORAD — Secondary Outcome

Results for the SCORAD are summarized in Table 18.

In the LIBERTY AD PRESCHOOL trial, there was a larger percent change from baseline to week 16 in SCORAD score observed in the dupilumab group compared to the placebo group; the LSM difference was –38.4% (95% CI, –46.65% to –30.21%; P < 0.0001).

In the LIBERTY AD PEDS trial, there was a larger percent change from baseline to week 16 in SCORAD score observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo were –32.6% |||| ||| ||||||| || |||||||| | | ||||||| and –30.4% |||| ||| ||||||| || |||||||| | | ||||||), respectively.

Patient Sleep Quality NRS — Secondary Outcome

Results for the patient sleep quality NRS are summarized in Table 18.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 in patients’ sleep quality NRS score observed in the dupilumab group compared to the placebo group; the LSM difference was 1.70 (95% CI, 1.09 to 2.32; P < 0.0001).

This was not an outcome in the LIBERTY AD PEDS trial.

Patient Skin Pain NRS — Secondary Outcome

Results for the patient skin pain NRS are summarized in Table 18.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 in patients’ skin pain NRS score observed in the dupilumab group compared to the placebo group; the LSM difference was –3.31 (95% CI, –4.03 to –2.60; P < 0.0001).

This was not an outcome in the LIBERTY AD PEDS trial.

Table 18: Summary of Other Disease-Related Outcome Results From Pivotal Studies — FAS

BSA = body surface area; CI = confidence interval; FAS = full analysis set; LSM = least squares mean; NA = not applicable; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; SE = standard error; TCS = topical corticosteroid.

^aThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg) as fixed factors.

^bThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), and baseline body mass (< 30 kg, ≥ 30 kg) as fixed factors.

^cP value has been adjusted for multiple testing.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

DFI — Secondary Outcomes

Results for the DFI are summarized in Table 19.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 in DFI score observed in the dupilumab group compared to the placebo group; the LSM difference was –7.80 (95% CI, –9.79 to –5.81; P < 0.0001).

In the LIBERTY AD PEDS trial, there was a larger change from baseline to week 16 in DFI score observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo was –3.98 |||| ||| ||||| || |||||| and –4.11 |||| ||| ||||| || ||||||, respectively.

CDLQI — Secondary Outcome

Results for the CDLQI are summarized in Table 19.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 in CDLQI score observed in the dupilumab group compared to the placebo group; the LSM difference was –7.5 (95% CI, –10.29 to –4.75; P < 0.0001).

In the LIBERTY AD PEDS trial, there was a larger change from baseline to week 16 in CDLQI score observed in both the dupilumab every 4 weeks and every 2 weeks groups compared to the placebo group; the LSM differences versus placebo were –4.2 |||| ||| ||||| || |||||| | | ||||||| and –4.3 |||| ||| ||||| || |||||| | | ||||||), respectively.

IDQOL — Secondary Outcome

Results for the IDQOL are summarized in Table 19.

In the LIBERTY AD PRESCHOOL trial, there was a larger change from baseline to week 16 in IDQOL score observed in the dupilumab group compared to the placebo group; the LSM difference was –8.96 (95% CI, –11.71 to –6.20; P < 0.0001).

This was not an outcome in the LIBERTY AD PEDS trial.

Table 19: Summary of HRQoL Results From Pivotal Studies — FAS

CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DFI = Dermatitis Family Impact; FAS = full analysis set; HRQoL = health-related quality of life; IDQOL = Infants’ Dermatitis Quality of Life Index; LSM = least squares mean; NA = not applicable; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SD = standard deviation; SE = standard error; TCS = topical corticosteroid.

^aThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), baseline disease severity (IGA 3, IGA 4), and baseline body mass (5 kg to < 15 kg, 15 kg to < 30 kg) as fixed factors.

^bThe CI and P value were based on treatment difference (dupilumab, placebo) of the LSM percent change using an analysis of covariance model with baseline measurement as covariate and the treatment, randomization strata (North America, Europe), and baseline body mass (< 30 kg, ≥ 30 kg) as fixed factors.

^cP value has been adjusted for multiple testing.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Harms

Harms are summarized in Table 20.

Adverse Events

More than half of patients in any treatment group for either trial experienced at least 1 TEAE. In both trials, more patients in the placebo group than the dupilumab groups experienced a TEAE and the most frequently reported TEAEs were atopic dermatitis, nasopharyngitis, and upper respiratory tract infection. In the LIBERTY AD PRESCHOOL trial, conjunctivitis occurred more frequently in the dupilumab group than the placebo group (3.6% and 0%, respectively), as did injection site erythema (1.2% and 0%, respectively). Similarly, in the LIBERTY AD PEDS trial, TEAEs that occurred more frequently in 1 or both of the every 4 weeks and every 2 weeks groups compared to the placebo group included conjunctivitis (4.2%, 5.7%, and 2.5%, respectively), injection site erythema (4.2%, 5.7%, and 1.7%, respectively), and nasopharyngitis (12.5%, 6.6%, and 6.7%, respectively).

Serious Adverse Events

There were 4 SAEs reported in the placebo group of the LIBERTY AD PRESCHOOL trial and none in the dupilumab group. In the LIBERTY AD PEDS trial, there were 2 SAEs reported in the dupilumab every 4 weeks group, 0 in the dupilumab every 2 weeks group, and 2 in the placebo group. No SAE was reported by more than 1 patient per trial.

Withdrawals Due to Adverse Events

Two patients stopped treatment due to AEs in the LIBERTY AD PRESCHOOL trial due to atopic dermatitis (dupilumab group) and nightmare (placebo group). Four patients stopped treatment due to AEs in the LIBERTY AD PEDS trial: 2 in the dupilumab every 2 weeks group due to food allergy and bacterial conjunctivitis and 2 in the placebo group due to atopic dermatitis and asthma.

Mortality

There were no patient deaths in either trial.

Notable Harms

There were no reports of anaphylactic reaction in either trial.

There were no reports of hypersensitivity in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, no treatment-related events of hypersensitivity or anaphylaxis occurred during the study.

There were no reports of helminthic infection in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, | ||||||| in each of the dupilumab every 4 weeks and placebo groups reported a helminthic infection and || |||||||| in the dupilumab every 2 weeks group.

In the LIBERTY AD PRESCHOOL trial, 3 patients in the dupilumab group and 0 patients in the placebo group reported conjunctivitis. In the LIBERTY AD PEDS trial, 5 patients, 7 patients, and 3 patients in the dupilumab every 4 weeks, dupilumab every 2 weeks, and placebo groups, respectively, reported conjunctivitis.

In the LIBERTY AD PRESCHOOL trial, 2 patients in the dupilumab group and 0 patients in the placebo group reported blepharitis. In the LIBERTY AD PEDS trial, | ||||||| and | |||||||| in the dupilumab every 2 weeks and placebo groups, respectively, reported blepharitis and no patients in the dupilumab every 4 weeks group.

In the LIBERTY AD PRESCHOOL trial, 1 patient in the dupilumab group and 0 patients in the placebo group reported keratitis. In the LIBERTY AD PEDS trial, 1 patient in the dupilumab every 2 weeks group reported keratitis and no patients in either the dupilumab every 4 weeks or placebo groups.

In the LIBERTY AD PRESCHOOL trial, 2 patients in the dupilumab group and 0 patients in the placebo group reported eosinophilia. In the LIBERTY AD PEDS trial, 1 patient in the dupilumab every 2 weeks group reported eosinophilia and no patients in either the dupilumab every 4 weeks or placebo groups.

Facial erythema was not captured in either trial.

Injection site pain was not captured in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, 3 patients, 2 patients, and 3 patients in the dupilumab every 4 weeks, dupilumab every 2 weeks, and placebo groups, respectively, reported injection site pain.

Table 20: Summary of Harms From Pivotal Studies — SAS

NR = not reported; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SAE = serious adverse event; SAS = safety analysis set; TCS = topical corticosteroid; TEAE = treatment-emergent adverse event.

Source: Sponsor’s Summary of Clinical Evidence, LIBERTY AD PRESCHOOL Clinical Study Report, and LIBERTY AD PEDS Clinical Study Report.^3,36,37 (Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.)

Critical Appraisal

Internal Validity

In both the LIBERTY AD PRESCHOOL and LIBERTY AD PEDS trials, randomization was stratified and performed centrally. Baseline characteristics were generally balanced between treatment groups with a few notable differences; however, these were mostly small imbalances that could have been due to chance. The clinical experts consulted by CADTH were not aware of any reason that the imbalances would change treatment outcomes. Therefore, the risk of bias arising from the randomization process was likely low.

Both pivotal trials used matching placebos and in the LIBERTY AD PRESCHOOL trial, blinding was adequate. During the LIBERTY AD PEDS trial, product was inadvertently delivered in an open-label manner and, consequently, 68 patients may have been unblinded to their treatment assignment. To mitigate the issue, the sponsor increased patient enrolment to maintain adequate power for the IGA and EASI-75 end points and added the mFAS supportive analyses that excluded data from these patients. The number of patients with major protocol deviations was similar across treatment groups for both trials and reasons were generally balanced, although more patients (6% to 7%) received protocol-excluded treatments in the LIBERTY AD PRESCHOOL trial. The proportion of patients with conjunctivitis, an AE associated with the drug, was higher in dupilumab groups, but the relatively low frequency (< 6% of patients in any group) make it less likely that this would result in unblinding of treatment allocations. Study and treatment discontinuations were also low (< 5% in any group) in both trials.

In both trials, a much smaller proportion of patients in the dupilumab groups used rescue treatment compared to the placebo groups: 19.3% (dupilumab) and 62.8% (placebo) of patients in the LIBERTY AD PRESCHOOL trial and 2.5% (dupilumab every 4 weeks), 4.9% (dupilumab every 2 weeks), and 19.2% (placebo) of patients in the LIBERTY AD PEDS trial. To disentangle the impact of rescue treatment on the assessment of treatment effect, the sponsor defined the following rule: “Values after first rescue treatment used were set to missing. Patients with missing values at week 16 due to rescue treatment, withdrawn consent, adverse event, and lack of efficacy were considered as nonresponders.”³⁷ According to this rule, upon first use of rescue treatment, a patient was counted as a nonresponder, regardless of the subsequent status of this patient. Therefore, there was no impact on responder analysis from the rescue treatment. However, the significant differences in rescue treatment use between dupilumab and placebo groups could impact how other outcomes (e.g., harms, HRQoL) that occurred after the use of rescue treatment were assessed.

Week 16 data for the primary outcome (IGA) and key secondary outcome (EASI-75) were missing for 3 (1.9%) patients in the LIBERTY AD PRESCHOOL trial and 9 (2.5%) patients in the LIBERTY AD PEDS trial. The small amount of missing data are not expected to have a major impact on the results and the risk of bias is low.

There was a lack of validity and reliability evidence in the literature for the itch NRS, percent BSA affected, and sleep quality NRS for patients with atopic dermatitis. Additionally, there were no MIDs identified from the literature for the IGA, percent BSA affected, sleep quality NRS, DFI, or IDQOL scores for patients with atopic dermatitis. However, the estimation of treatment effect based on the IGA and EASI are likely valid and reliable based on the current available literature. Overall, the treatment effects, as observed in the 2 trials and by various different outcome measures, were consistent.

External Validity

According to the clinical experts consulted by CADTH, the patients in both pivotal trials were similar to those seen in practice who could receive dupilumab. The LIBERTY AD PRESCHOOL trial included patients with moderate-to-severe atopic dermatitis, while the LIBERTY AD PEDS trial included only patients with severe atopic dermatitis. The clinical experts were of the opinion that the results from the latter trial would be generalizable to patients with moderate atopic dermatitis based on trial results for age groups both younger and older that included patients with moderate disease but noted that patients with severe disease have a higher ceiling for improvement on continuous efficacy outcomes. The experts suggested that, in practice, some patients with an EASI score less than 16 may be eligible for dupilumab, and this is supported by the literature showing that patients with moderate atopic dermatitis can have an EASI score as low as 6.^34,35 For example, a patient with severe lesions but low percent BSA affected or with lesions localized to special areas (e.g., hands, feet, scalp), whose disease is not adequately controlled with prescription topical therapies, could have a low EASI score and be treated with dupilumab. It was unclear if patients in whom topical prescription therapies are not advisable were included in the trials, though according to the clinical experts consulted by CADTH, this would be a very small proportion of patients and would not greatly impact generalizability to the population who could receive dupilumab. Patients with a history of important side effects to TCSs were excluded from the trials, but the clinical experts stated that side effects are rare when TCSs are used properly and that it would be reasonable for patients who cannot tolerate TCSs or other topical therapies to receive dupilumab. This could be a gap in the evidence for dupilumab, but would likely have a minor impact.

The clinical experts confirmed that the types of treatments (both background therapies and rescue therapies) used in the trials were acceptable; however, the way in which nonresponders were defined in the trials was inconsistent with clinical practice. In both pivotal trials, TCS was the only permitted concomitant treatment; other topical therapies such as TCIs and crisaborole had to be discontinued at least 2 weeks before baseline (or were used as rescue treatment) and prescription moisturizers could not be initiated during the trial. This differs from clinical practice and, as per the clinical experts, non-TCS therapies would also be acceptable add-on treatment while receiving dupilumab. The clinical experts thought that the use of rescue treatments, as defined in the trials, would not necessarily mean a patient was a nonresponder and that higher-potency TCSs, other prescription topical treatments, and a short course of systemic therapies (< 8 weeks) would be acceptable to use alongside dupilumab. They also stated that patients may improve while on dupilumab (i.e., be responders), but may still require additional therapy.

The clinical experts stated that although the trials’ assessments are common in clinical trials, they are generally not used in practice. Instead, clinicians often use a gestalt approach, asking how a patient feels and observing clinical changes. The assessments used in the trials may provide an approximation of what clinicians use in practice and are relevant to the most important treatment goals. Based on the input from patient groups and what was highlighted as being the greatest concerns (i.e., symptom management, HRQoL, and safety of systemic treatments), the trial outcomes were relevant to patients. The patient group input also noted that topical regimens are burdensome to administer. It is unclear from the trial if dupilumab injections every 2 weeks or every 4 weeks (with or without topical therapies) address the need for a simpler treatment, particularly if patients or caregivers cannot perform at-home injections (all patients in the LIBERTY AD PRESCHOOL trial and those whose caregivers were uncomfortable with at-home administration in the LIBERTY AD PEDS trial) or if patients are especially afraid of needles. Based on their experience, the experts felt that the trade-off between topical and injectable therapies may be acceptable for some and that many patients who improve on dupilumab are willing to continue. Lastly, it should be noted that the pivotal trials were 16 weeks long and provide short-term results for what is expected to be a long-term treatment.

LTE Studies

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Description of Studies

Study 1434 is an ongoing, global, open-label, single-group, LTE study of patients aged 6 months to younger than 18 years with atopic dermatitis.^38,39 The aim of the study is to assess the long-term safety and efficacy of dupilumab following the parent LIBERTY trials for dupilumab for up to 260 weeks of treatment. Presented in this summary are data for patients aged 6 months to younger than 6 years (N = 180) and patients aged 6 years to younger than 12 years (N = 368) who participated in the pivotal trials described in the main report. The primary outcome was the incidence rate (events per patient-year) of TEAEs. The study started on October 15, 2015, and results presented in this document were based on a prespecified second-step analysis conducted on data from patients aged 6 years to younger than 12 years (data cut-off on July 22, 2019) and from a third-step analysis conducted on data from patients aged 6 months to younger than 6 years (data cut-off on July 31, 2021).

Populations

Patients were eligible to enrol in Study 1434 if they were aged 6 months to younger than 18 years and completed at least 50% of the visits during the treatment and follow-up periods in 1 of the parent dupilumab studies. Patients were excluded if they developed a SAE deemed related to the treatment during their participation in a parent study, or an AE related to the study drug that led to discontinuation or withdrawal by the investigator from the study because of noncompliance and/or inability to complete required study assessments. Patients who had sustained disease remission, as defined by maintenance of an IGA score of 0 or 1 continuously for a 12-week period, after week 40, were discontinued from dupilumab. Patients were closely monitored after discontinuing due to disease remission and upon relapse (IGA ≥ 2), dupilumab could be reinitiated.

Interventions

Dupilumab was provided at the following doses and dosing schedules:

• body mass 60 kg or greater: 300 mg every 2 weeks

• body mass 30 kg to less than 60 kg: 200 mg every 2 weeks

• body mass 15 kg to less than 30 kg: 300 mg every 4 weeks

• body mass 5 kg to less than 15 kg: 200 mg every 4 weeks.

Outcomes

The primary end points in the study were the incidence and rate of TEAEs from baseline through the last study visit. Incidence was defined as:

• TEAE rate per patient-year

• number of patients with at least 1 TEAE per patient-year.

The secondary end points included:

• incidence of treatment-emergent SAEs from baseline through the last study visit

• incidence of TEAEs of special interest from baseline through the last study visit

• proportion of patients with an IGA score of 0 or 1 at all in-clinic visits postbaseline

• proportion of patients with EASI-75 response (from baseline of parent study) at all in-clinic visits postbaseline

• change and percent change from baseline in EASI at all in-clinic visits postbaseline

• change from baseline in percent BSA affected by atopic dermatitis at all in-clinic visits postbaseline

• percent change from baseline in SCORAD score at all in-clinic visits postbaseline

• change from baseline in CDLQI score for patients aged 4 years or older at all in-clinic visits postbaseline in which the assessments were planned

• change from baseline in IDQOL score for patients aged younger than 4 years at all in-clinic visits postbaseline in which the assessments were planned

• assessment of maintenance of treatment effect:

  • proportion of responders (defined as patients with IGA 0 or 1) who maintain an IGA score of 0 or 1 during at least 75% of the subsequent visits during the treatment period

  • for responders (defined as patients with IGA 0 or 1), median percentage of subsequent visits during the treatment period in which an IGA score of 0 or 1 is maintained

• assessment of flares:

  • number and annualized event rate of atopic dermatitis flares during the study

  • proportion of patients with at least 1 flare during the study

• assessment of well-controlled weeks:

  • proportion of well-controlled weeks during the study.

The sponsor also assessed the following end points; however, the sponsor stated that these end points were not analyzed in the interim Clinical Study Report as the number of patients was too small to conduct meaningful analyses, and they would be available in the final Clinical Study Report:

• relapse during off-treatment period by measuring the following variables:

  • proportion of patients experiencing relapse

  • annualized event rate of relapse during the off-treatment period

  • median time to first relapse

• assessment of potential rebound (defined as worsening of EASI score [i.e., at least 25% increase from baseline of the parent study] within 12 weeks after the study treatment had been discontinued):

  • proportion of patients experiencing potential rebound

  • annualized event rate of potential rebound during the off-treatment period

  • median time to first potential rebound (from last dose of study drug).

Safety Evaluation Plan

The investigator recorded all AEs that occurred from the time of informed consent to the end of the study. All SAEs, regardless of assessment of causal relationship to the study drug, were reported to the sponsor within 24 hours.

An AE was any untoward medical occurrence in a patient administered a study drug, regardless of relationship to the study drug. Therefore, an AE was any unfavourable and unintended sign (including abnormal laboratory finding), symptom, or disease, which was temporally associated with the use of a study drug. An AE also included any worsening (i.e., any clinically significant change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the study drug.

An SAE was any untoward medical occurrence that at any dose:

• resulted in death

• was life-threatening

• required inpatient hospitalization or prolongation of existing hospitalization

• resulted in persistent or significant disability or incapacity

• was a congenital anomaly or birth defect

• was an important medical event.

Notable harms that were prespecified by the sponsor and confirmed by the clinical experts consulted by CADTH are summarized in this review.

Statistical Analysis

No hypothesis-testing statistical analysis was planned. The sponsor did a safety analysis that included all patients who received any study drug.

Baseline Characteristics

Patient characteristics at baseline are summarized in Table 21. For patients aged 6 months to younger than 6 years, 64.4% were male and 35.6% were female and the mean age was 3.86 years (SD = 1.32 years). Approximately, ||||| of patients had an IGA score of 0 to 2, ||||| had an IGA score of 3, and ||||| had an IGA score of 4. The mean baseline EASI, BSA, and SCORAD scores were 17.29 (SD = 14.47), |||| ||| | ||||||, and 46.8 (SD = 22.81), respectively. Overall, ||||| of patients reported prior use of systemic corticosteroid and/or systemic nonsteroidal immunosuppressants, of whom ||||| received systemic corticosteroids and ||||| patients received prior systemic nonsteroidal immunosuppressants. The most commonly used nonsteroidal immunosuppressant was cyclosporine (|||||).

For patients aged 6 years to younger than 12 years, ||||| of patients were male and ||||| were female and the mean age was ||| ||||| ||| | |||| ||||||. Approximately half of patients had an IGA score of 0 to 2, 29.9% had an IGA score of 3, and 19.6% had an IGA score of 4. The mean baseline EASI, BSA, and SCORAD scores were 15.70 (SD = 15.88), 28.6 (SD = 25.52); and |||| ||| | ||||||, respectively. Overall, ||||| of patients reported prior use of systemic corticosteroid and/or systemic nonsteroidal immunosuppressants, of whom ||||| received systemic corticosteroids and ||||| patients received prior systemic nonsteroidal immunosuppressants. The most commonly used nonsteroidal immunosuppressant was cyclosporine (|||||).

Table 21: Summary of Baseline and Disease Characteristics — Study 1434